SBML generated from Reactome version 77 on 6/24/21 2:02 PM using JSBML version 1.5.
Mast cells (MC) are distributed in tissues throughout the human body and have long been recognized as key cells of type I hypersensitivity reactions. They also play important roles in inflammatory and immediate allergic reactions. Activation through FCERI-bound antigen-specific IgE causes release of potent inflammatory mediators, such as histamine, proteases, chemotactic factors, cytokines and metabolites of arachidonic acid that act on the vasculature, smooth muscle, connective tissue, mucous glands and inflammatory cells (Borish and Joseph 1992, Amin 2012, Metcalfe et al. 1993). FCERI is a multimeric cell-surface receptor that binds the Fc fragment of IgE with high affinity. On mast cells and basophils FCERI exists as a tetrameric complex consisting of one alpha-chain, one beta-chain, and two disulfide-bonded gamma-chains, and on dendritic cells, Langerhans cells, macrophages, and eosinophils it exists as a trimeric complex with one alpha-chain and two disulfide-bonded gamma-chains (Wu 2011, Kraft and Kinet 2007). FCERI signaling in mast cells includes a network of signaling molecules and adaptor proteins. These molecules coordinate ultimately leading to effects on degranulation, eicosanoid production, and cytokine and chemokine production and cell migration and adhesion, growth and survival.The first step in FCERI signaling is the phosphorylation of the tyrosine residues in the ITAM of both the beta and the gamma subunits of the FCERI by LYN, which is bound to the FCERI beta-chain. The phosphorylated ITAM then recruits the protein tyrosine kinase SYK (spleen tyrosine kinase) which then phosphorylates the adaptor protein LAT. Phosphorylated LAT (linker for activation of T cells) acts as a scaffolding protein and recruits other cytosolic adaptor molecules GRB2 (growth-factor-receptor-bound protein 2), GADS (GRB2-related adaptor protein), SHC (SRC homology 2 (SH2)-domain-containing transforming protein C) and SLP76 (SH2-domain-containing leukocyte protein of 76 kDa), as well as the exchange factors and adaptor molecules VAV and SOS (son of sevenless homologue), and the signalling enzyme phospholipase C gamma1 (PLC-gamma1). Tyrosoine phosphorylation of enzymes and adaptors, including VAV, SHC GRB2 and SOS stimulate small GTPases such as RAC, RAS and RAF. These pathways lead to activation of the ERK, JNK and p38 MAP kinases, histamine release and cytokine production. FCERI activation also triggers the phosphorylation of PLC-gamma which upon membrane localisation hydrolyse PIP2 to form IP3 and 1,2-diacylglycerol (DAG) - second messengers that release Ca2+ from internal stores and activate PKC, respectively. Degranulation or histamine release follows the activation of PLC-gamma and protein kinase C (PKC) and the increased mobilization of calcium (Ca2+). Receptor aggregation also results in the phosphorylation of adaptor protein NTAL/LAT2 which then recruits GAB2. PI3K associates with phosphorylated GAB2 and catalyses the formation of PIP3 in the membrane, which attracts many PH domain proteins like BTK, PLC-gamma, AKT and PDK. PI3K mediated activation of AKT then regulate the mast cell proliferation, development and survival (Gu et al. 2001).
Derived from a Reactome Complex. Here is Reactomes nested structure for this complex: (18035, Q9Y4K3, Q04759, Q9UDY8, O95999, Q9BXL7). Reactome uses a nested structure for complexes, which cannot be fully represented in SBML Level 3 Version 1 core
Derived from a Reactome DefinedSet. This is a list of alternative entities, any of which can perform the given function
Derived from a Reactome Complex. Here is Reactomes nested structure for this complex: (P29353, P62993, Q07889, O43561). Reactome uses a nested structure for complexes, which cannot be fully represented in SBML Level 3 Version 1 core
Derived from a Reactome EntityWithAccessionedSequence. This is a protein
Derived from a Reactome EntityWithAccessionedSequence. This is a protein
Derived from a Reactome EntityWithAccessionedSequence. This is a protein
Derived from a Reactome Complex. Here is Reactomes nested structure for this complex: (P29353, P62993, Q07889). Reactome uses a nested structure for complexes, which cannot be fully represented in SBML Level 3 Version 1 core
Derived from a Reactome Complex. Here is Reactomes nested structure for this complex: (O43865, 4x16595, 4xQ14571, 4xQ14643, 57540, 4xQ14573). Reactome uses a nested structure for complexes, which cannot be fully represented in SBML Level 3 Version 1 core
Derived from a Reactome Complex. Here is Reactomes nested structure for this complex: (Q04206, P25963, P19838). Reactome uses a nested structure for complexes, which cannot be fully represented in SBML Level 3 Version 1 core
Derived from a Reactome Polymer. Molecules that consist of an indeterminate number of repeated units. Includes complexes whose stoichiometry is variable or unknown. The repeated unit(s) is(are) identified in the repeatedUnit slot
Derived from a Reactome Complex. Here is Reactomes nested structure for this complex: (29105, 29034, P0DP23, 8x29108, Q08209, P63098, P16298). Reactome uses a nested structure for complexes, which cannot be fully represented in SBML Level 3 Version 1 core
Derived from a Reactome SimpleEntity. This is a small compound
Derived from a Reactome Complex. Here is Reactomes nested structure for this complex: (Q9Y6K9, O14920, O15111). Reactome uses a nested structure for complexes, which cannot be fully represented in SBML Level 3 Version 1 core
Derived from a Reactome SimpleEntity. This is a small compound
Derived from a Reactome Complex. Here is Reactomes nested structure for this complex: (Q13404, P61088). Reactome uses a nested structure for complexes, which cannot be fully represented in SBML Level 3 Version 1 core
Derived from a Reactome Complex. Here is Reactomes nested structure for this complex: (P29353, P62993, Q07889, P52735, P19174, P42681, P42680, 16618, Q08881, Q9UKW4, P15498, Q06187, O43561, Q13094, P16885, O75791). Reactome uses a nested structure for complexes, which cannot be fully represented in SBML Level 3 Version 1 core
Derived from a Reactome Complex. Here is Reactomes nested structure for this complex: (Q5NV64, P01615, Q5NV79, P01825, 2xP30273, P01762, P01766, Q5NV61, P01817, A0A075B6S6, P01718, Q5NV81, P01772, P01834, P01709, A0A075B6P5, Q5NV91, Q01362, P01824, P01699, Q5NV65, P01601, Q5NV68, P07948, P01854, P0DOY2, 2xP23083, P12319, P04432, P01593, P01814, Q5NV86, Q5NV83, P01767, Q5NV87, P01703, P0CG04, P01594, P01611, Q5NV75, P01624, Q5NV89, P06315, A2NXD2, P06331, P01763, A0M8Q6, P04433, P04430, P01597, P04211, Q5NV80, P01742, A2NJV5, P01704, Q5NV85, Q5NV90, Q5NV67, P01602, P0CF74, Q5NV82, P0DOY3, Q6PIL0, P01717, P80748, Q5NV66, P01619, P01743, P01764, P01700, A0A0C4DH25, P01614, Q5NV69, P01782, Q5NV92, P43405, P01599, P01714, P01768, P06312, A2KUC3, A0A0C4DH73, P01715, P01706, P01780, P01721, Q5NV84, Q5NV62, P01701, P06310, P01705). Reactome uses a nested structure for complexes, which cannot be fully represented in SBML Level 3 Version 1 core
Derived from a Reactome DefinedSet. This is a list of alternative entities, any of which can perform the given function
The most studied polyubiquitin chains - lysine48-linked - target proteins for destruction
Derived from a Reactome EntityWithAccessionedSequence. This is a protein
Derived from a Reactome Complex. Here is Reactomes nested structure for this complex: (P62195, O14818, A5LHX3, P40306, P17980, P51665, O00232, O00231, O75832, P49721, O43242, P35998, P28062, P25787, O00233, P62191, O00487, Q13200, P25789, P20618, P28072, Q06323, P48556, Q15008, Q99436, Q99460, P28065, Q9UL46, P55036, P28066, Q14997, P25788, P28070, P25786, P60896, Q92530, P60900, P28074, Q16401, Q8TAA3, P49720, Q9UNM6, P62333, P61289, P43686). Reactome uses a nested structure for complexes, which cannot be fully represented in SBML Level 3 Version 1 core
Derived from a Reactome EntityWithAccessionedSequence. This is a protein
Derived from a Reactome EntityWithAccessionedSequence. This is a protein
Derived from a Reactome SimpleEntity. This is a small compound
Derived from a Reactome EntityWithAccessionedSequence. This is a protein
Derived from a Reactome SimpleEntity. This is a small compound
Derived from a Reactome Complex. Here is Reactomes nested structure for this complex: (Q9Y6K9, O14920, O15111). Reactome uses a nested structure for complexes, which cannot be fully represented in SBML Level 3 Version 1 core
Co-immunoprecipitation studies and size exclusion chromatography analysis indicate that the high molecular weight (around 700 to 900 kDa) IKK complex is composed of two kinase subunits (IKK1/CHUK/IKBKA and/or IKK2/IKBKB/IKKB) bound to a regulatory gamma subunit (IKBKG/NEMO) (Rothwarf DMet al. 1998; Krappmann D et al. 2000; Miller BS and Zandi E 2001). Variants of the IKK complex containing IKBKA or IKBKB homodimers associated with NEMO may also exist. Crystallographic and quantitative analyses of the binding interactions between N-terminal NEMO and C-terminal IKBKB fragments showed that IKBKB dimers would interact with NEMO dimers resulting in 2:2 stoichiometry (Rushe M et al. 2008). Chemical cross-linking and equilibrium sedimentation analyses of IKBKG (NEMO) suggest a tetrameric oligomerization (dimers of dimers) (Tegethoff S et al. 2003). The tetrameric NEMO could sequester four kinase molecules, yielding an 2xIKBKA:2xIKBKB:4xNEMO stoichiometry (Tegethoff S et al. 2003). The above data suggest that the core IKK complex consists of an IKBKA:IKBKB heterodimer associated with an IKBKG dimer or higher oligomeric assemblies. However, the exact stoichiometry of the IKK complex remains unclear.
Derived from a Reactome SimpleEntity. This is a small compound
Derived from a Reactome Complex. Here is Reactomes nested structure for this complex: (18035, Q04759). Reactome uses a nested structure for complexes, which cannot be fully represented in SBML Level 3 Version 1 core
Derived from a Reactome OtherEntity. Entities that we are unable or unwilling to describe in chemical detail and cannot be put in any other class. Can be used to represent complex structures in the cell that take part in a reaction but which we cannot or do not want to define molecularly, e.g. cell membrane, Holliday structure
Derived from a Reactome Complex. Here is Reactomes nested structure for this complex: (P29353, P62993, Q07889, P19174, O43561, Q13094, P16885, O75791). Reactome uses a nested structure for complexes, which cannot be fully represented in SBML Level 3 Version 1 core
Derived from a Reactome Complex. Here is Reactomes nested structure for this complex: (18035, Q04759). Reactome uses a nested structure for complexes, which cannot be fully represented in SBML Level 3 Version 1 core
Derived from a Reactome Complex. Here is Reactomes nested structure for this complex: (18035, Q9Y4K3, Q15750, Q04759, Q9UDY8, O95999, Q9NYJ8, O43318, Q8N5C8, Q9BXL7). Reactome uses a nested structure for complexes, which cannot be fully represented in SBML Level 3 Version 1 core
Derived from a Reactome Complex. Here is Reactomes nested structure for this complex: (P12319, 2xP30273, Q01362). Reactome uses a nested structure for complexes, which cannot be fully represented in SBML Level 3 Version 1 core
Derived from a Reactome Complex. Here is Reactomes nested structure for this complex: (Q9Y6K9, O14920, O15111). Reactome uses a nested structure for complexes, which cannot be fully represented in SBML Level 3 Version 1 core
Derived from a Reactome CandidateSet. A list of entities, one or more of which might perform the given function
Derived from a Reactome SimpleEntity. This is a small compound
Derived from a Reactome Complex. Here is Reactomes nested structure for this complex: (18035, Q9Y4K3, Q15750, Q04759, Q9UDY8, O95999, Q9NYJ8, O43318, Q8N5C8, Q9BXL7). Reactome uses a nested structure for complexes, which cannot be fully represented in SBML Level 3 Version 1 core
Derived from a Reactome Complex. Here is Reactomes nested structure for this complex: (P01116, P01112, P01116, 15996, P01111). Reactome uses a nested structure for complexes, which cannot be fully represented in SBML Level 3 Version 1 core
Derived from a Reactome EntityWithAccessionedSequence. This is a protein
Derived from a Reactome ProteinDrug. A drug
Derived from a Reactome EntityWithAccessionedSequence. This is a protein
Derived from a Reactome EntityWithAccessionedSequence. This is a protein
Derived from a Reactome Complex. Here is Reactomes nested structure for this complex: (P62993, Q07889). Reactome uses a nested structure for complexes, which cannot be fully represented in SBML Level 3 Version 1 core
Derived from a Reactome Complex. Here is Reactomes nested structure for this complex: (P63000, 17552). Reactome uses a nested structure for complexes, which cannot be fully represented in SBML Level 3 Version 1 core
Derived from a Reactome DefinedSet. This is a list of alternative entities, any of which can perform the given function
Derived from a Reactome Complex. Here is Reactomes nested structure for this complex: (Q9UDY8, O95999). Reactome uses a nested structure for complexes, which cannot be fully represented in SBML Level 3 Version 1 core
Derived from a Reactome Complex. Here is Reactomes nested structure for this complex: (18035, Q04759, Q9UDY8, O95999, Q9BXL7). Reactome uses a nested structure for complexes, which cannot be fully represented in SBML Level 3 Version 1 core
Derived from a Reactome Complex. Here is Reactomes nested structure for this complex: (P29353, P62993, Q07889, P52735, P19174, P42681, P42680, 16618, Q08881, Q9UKW4, P15498, Q06187, O43561, Q13094, P16885, O75791). Reactome uses a nested structure for complexes, which cannot be fully represented in SBML Level 3 Version 1 core
Derived from a Reactome Complex. Here is Reactomes nested structure for this complex: (18035, Q04759). Reactome uses a nested structure for complexes, which cannot be fully represented in SBML Level 3 Version 1 core
Derived from a Reactome DefinedSet. This is a list of alternative entities, any of which can perform the given function
Derived from a Reactome EntityWithAccessionedSequence. This is a protein
Derived from a Reactome Complex. Here is Reactomes nested structure for this complex: (P05412, P01100). Reactome uses a nested structure for complexes, which cannot be fully represented in SBML Level 3 Version 1 core
Derived from a Reactome Complex. Here is Reactomes nested structure for this complex: (16618, P29353, Q9UQC2, Q9GZY6, P62993, Q07889). Reactome uses a nested structure for complexes, which cannot be fully represented in SBML Level 3 Version 1 core
Derived from a Reactome EntityWithAccessionedSequence. This is a protein
Derived from a Reactome EntityWithAccessionedSequence. This is a protein
Derived from a Reactome EntityWithAccessionedSequence. This is a protein
Derived from a Reactome Complex. Here is Reactomes nested structure for this complex: (P29353, Q9GZY6, P62993, Q07889). Reactome uses a nested structure for complexes, which cannot be fully represented in SBML Level 3 Version 1 core
Derived from a Reactome SimpleEntity. This is a small compound
Derived from a Reactome EntityWithAccessionedSequence. This is a protein
Derived from a Reactome SimpleEntity. This is a small compound
Derived from a Reactome EntityWithAccessionedSequence. This is a protein
Derived from a Reactome Complex. Here is Reactomes nested structure for this complex: (Q15750, Q9NYJ8, O43318, Q8N5C8). Reactome uses a nested structure for complexes, which cannot be fully represented in SBML Level 3 Version 1 core
Derived from a Reactome Complex. Here is Reactomes nested structure for this complex: (Q13616, P63208, Q9UKB1, Q9Y297). Reactome uses a nested structure for complexes, which cannot be fully represented in SBML Level 3 Version 1 core
Derived from a Reactome SimpleEntity. This is a small compound
Derived from a Reactome EntityWithAccessionedSequence. This is a protein
Derived from a Reactome Complex. Here is Reactomes nested structure for this complex: (P29353, P62993, Q07889, P19174, O43561, Q13094, P16885, O75791). Reactome uses a nested structure for complexes, which cannot be fully represented in SBML Level 3 Version 1 core
Derived from a Reactome Complex. Here is Reactomes nested structure for this complex: (Q5NV64, P01615, Q5NV79, P01825, P01762, P01766, Q5NV61, P01817, A0A075B6S6, P01718, Q5NV81, P01772, P01834, P01709, A0A075B6P5, Q5NV91, P01824, P01699, Q5NV65, P01601, Q5NV68, P01854, P0DOY2, 2xP23083, P04432, P01593, P01814, Q5NV86, Q5NV83, P01767, Q5NV87, P01703, P0CG04, P01594, P01611, Q5NV75, P01624, Q5NV89, P06315, A2NXD2, P06331, P01763, A0M8Q6, P04433, P04430, P01597, P04211, Q5NV80, P01742, A2NJV5, P01704, Q5NV85, Q5NV90, Q5NV67, P01602, P0CF74, Q5NV82, P0DOY3, Q6PIL0, P01717, P80748, Q5NV66, P01619, P01743, P01764, P01700, A0A0C4DH25, P01614, Q5NV69, P01782, Q5NV92, P01599, P01714, P01768, P06312, A2KUC3, A0A0C4DH73, P01715, P01706, P01780, P01721, Q5NV84, Q5NV62, P01701, P06310, P01705). Reactome uses a nested structure for complexes, which cannot be fully represented in SBML Level 3 Version 1 core
针对抗体高度可变的本质proteins, this biological object is an approximate and fragmented representation of an IgM/IgD antibody, given the limitations of Ig chain enumeration in UniProt. A single mRNA transcript is alternatively spliced to give either IgM or IgD. Thus unactivated B cells contain both classes of antibody.
Derived from a Reactome EntityWithAccessionedSequence. This is a protein
Derived from a Reactome EntityWithAccessionedSequence. This is a protein
Derived from a Reactome Complex. Here is Reactomes nested structure for this complex: (29105, 29034, P0DP23, Q12968, 8x29108, O95644, Q08209, P63098, P16298, Q13469). Reactome uses a nested structure for complexes, which cannot be fully represented in SBML Level 3 Version 1 core
Derived from a Reactome Complex. Here is Reactomes nested structure for this complex: (Q04206, P25963, P19838). Reactome uses a nested structure for complexes, which cannot be fully represented in SBML Level 3 Version 1 core
Derived from a Reactome CandidateSet. A list of entities, one or more of which might perform the given function
Rap1 can be activated by certain GEFs that respond to calcium and diacylglycerol (CalDAG-GEFs).
Derived from a Reactome Complex. Here is Reactomes nested structure for this complex: (29105, 29034, P0DP23, Q12968, 8x29108, O95644, Q08209, P63098, P16298, Q13469). Reactome uses a nested structure for complexes, which cannot be fully represented in SBML Level 3 Version 1 core
Derived from a Reactome DefinedSet. This is a list of alternative entities, any of which can perform the given function
Derived from a Reactome EntityWithAccessionedSequence. This is a protein
Derived from a Reactome Complex. Here is Reactomes nested structure for this complex: (16618, 3xQ9Y4K3, 3xQ9UDY8, 3xO95999, 16152, 3xQ9BXL7, O15530). Reactome uses a nested structure for complexes, which cannot be fully represented in SBML Level 3 Version 1 core
Derived from a Reactome EntityWithAccessionedSequence. This is a protein
Derived from a Reactome Complex. Here is Reactomes nested structure for this complex: (Q5NV64, P01615, Q5NV79, P01825, 2xP30273, P01762, P01766, Q5NV61, P01817, A0A075B6S6, P01718, Q5NV81, P01772, P01834, P01709, A0A075B6P5, Q5NV91, P01824, Q01362, P01699, Q5NV65, P01601, Q5NV68, P01854, P0DOY2, 2xP23083, P12319, P04432, P01593, P01814, Q5NV86, Q5NV83, P01767, Q5NV87, P01703, P0CG04, P01594, P01611, Q5NV75, P01624, Q5NV89, P06315, A2NXD2, P06331, P01763, A0M8Q6, P04433, P04430, P01597, P04211, Q5NV80, P01742, A2NJV5, P01704, Q5NV85, Q5NV90, Q5NV67, P01602, P0CF74, Q5NV82, P0DOY3, Q6PIL0, P01717, P80748, Q5NV66, P01619, P01743, P01764, P01700, A0A0C4DH25, P01614, Q5NV69, P01782, Q5NV92, P01599, P01714, P01768, P06312, A2KUC3, A0A0C4DH73, P01715, P01706, P01780, P01721, Q5NV84, Q5NV62, P01701, P06310, P01705). Reactome uses a nested structure for complexes, which cannot be fully represented in SBML Level 3 Version 1 core
Derived from a Reactome DefinedSet. This is a list of alternative entities, any of which can perform the given function
Derived from a Reactome Complex. Here is Reactomes nested structure for this complex: (16618, O00459, Q9UQC2, P29353, Q9GZY6, P27986, P62993, Q07889, P42338, P42336). Reactome uses a nested structure for complexes, which cannot be fully represented in SBML Level 3 Version 1 core
Derived from a Reactome EntityWithAccessionedSequence. This is a protein
Derived from a Reactome Complex. Here is Reactomes nested structure for this complex: (4x16595, 4xQ14571, 4xQ14643, 4xQ14573). Reactome uses a nested structure for complexes, which cannot be fully represented in SBML Level 3 Version 1 core
Derived from a Reactome SimpleEntity. This is a small compound
Derived from a Reactome Complex. Here is Reactomes nested structure for this complex: (18035, Q7LDG7, Q8TDF6, 29108, O95267). Reactome uses a nested structure for complexes, which cannot be fully represented in SBML Level 3 Version 1 core
Derived from a Reactome Complex. Here is Reactomes nested structure for this complex: (Q5NV64, P01615, Q5NV79, P01825, 2xP30273, P01762, P01766, Q5NV61, P01817, A0A075B6S6, P01718, Q5NV81, P01772, P01834, P01709, A0A075B6P5, Q5NV91, Q01362, P01824, P01699, Q5NV65, P01601, Q5NV68, P07948, P01854, P0DOY2, 2xP23083, P12319, P04432, P01593, P01814, Q5NV86, Q5NV83, P01767, Q5NV87, P01703, P0CG04, P01594, P01611, Q5NV75, P01624, Q5NV89, P06315, A2NXD2, P06331, P01763, A0M8Q6, P04433, P04430, P01597, P04211, Q5NV80, P01742, A2NJV5, P01704, Q5NV85, Q5NV90, Q5NV67, P01602, P0CF74, Q5NV82, P0DOY3, Q6PIL0, P01717, P80748, Q5NV66, P01619, P01743, P01764, P01700, A0A0C4DH25, P01614, Q5NV69, P01782, Q5NV92, P43405, P01599, P01714, P01768, P06312, A2KUC3, A0A0C4DH73, P01715, P01706, P01780, P01721, Q5NV84, Q5NV62, P01701, P06310, P01705). Reactome uses a nested structure for complexes, which cannot be fully represented in SBML Level 3 Version 1 core
Derived from a Reactome Complex. Here is Reactomes nested structure for this complex: (P29353, P62993, Q07889, O43561, Q13094, O75791). Reactome uses a nested structure for complexes, which cannot be fully represented in SBML Level 3 Version 1 core
Derived from a Reactome EntityWithAccessionedSequence. This is a protein
Derived from a Reactome Complex. Here is Reactomes nested structure for this complex: (P29353, P62993, Q07889, P52735, P19174, P42681, P42680, 16618, Q08881, Q9UKW4, P15498, Q06187, O43561, Q13094, P16885, O75791). Reactome uses a nested structure for complexes, which cannot be fully represented in SBML Level 3 Version 1 core
Derived from a Reactome Complex. Here is Reactomes nested structure for this complex: (16618, Q9UQC2, P29353, Q9GZY6, P62993, Q07889). Reactome uses a nested structure for complexes, which cannot be fully represented in SBML Level 3 Version 1 core
Derived from a Reactome DefinedSet. This is a list of alternative entities, any of which can perform the given function
Derived from a Reactome Complex. Here is Reactomes nested structure for this complex: (P29353, P63000, P62993, Q07889, P52735, P19174, 16618, Q9UKW4, P15498, 15996, O43561, Q13094, P16885, O75791). Reactome uses a nested structure for complexes, which cannot be fully represented in SBML Level 3 Version 1 core
Derived from a Reactome Complex. Here is Reactomes nested structure for this complex: (P29353, P62993, Q9UKW4, P15498, Q07889, P52735, P19174, O43561, Q13094, P16885, O75791). Reactome uses a nested structure for complexes, which cannot be fully represented in SBML Level 3 Version 1 core
Derived from a Reactome SimpleEntity. This is a small compound
Derived from a Reactome Complex. Here is Reactomes nested structure for this complex: (P0DP23, 4x29108). Reactome uses a nested structure for complexes, which cannot be fully represented in SBML Level 3 Version 1 core
Derived from a Reactome Complex. Here is Reactomes nested structure for this complex: (Q13094, O75791). Reactome uses a nested structure for complexes, which cannot be fully represented in SBML Level 3 Version 1 core
Derived from a Reactome Complex. Here is Reactomes nested structure for this complex: (Q04206, P19838). Reactome uses a nested structure for complexes, which cannot be fully represented in SBML Level 3 Version 1 core
Derived from a Reactome SimpleEntity. This is a small compound
Derived from a Reactome DefinedSet. This is a list of alternative entities, any of which can perform the given function
Derived from a Reactome Complex. Here is Reactomes nested structure for this complex: (Q5NV64, P01615, Q5NV79, P01825, 2xP30273, P01762, P01766, Q5NV61, P01817, A0A075B6S6, P01718, Q5NV81, P01772, P01834, P01709, A0A075B6P5, Q5NV91, P01824, Q01362, P01699, Q5NV65, P01601, Q5NV68, P01854, P0DOY2, 2xP23083, P12319, P04432, P01593, P01814, Q5NV86, Q5NV83, P01767, Q5NV87, P01703, P0CG04, P01594, P01611, Q5NV75, P01624, Q5NV89, P06315, A2NXD2, P06331, P01763, A0M8Q6, P04433, P04430, P01597, P04211, Q5NV80, P01742, A2NJV5, P01704, Q5NV85, Q5NV90, Q5NV67, P01602, P0CF74, Q5NV82, P0DOY3, Q6PIL0, P01717, P80748, Q5NV66, P01619, P01743, P01764, P01700, A0A0C4DH25, P01614, Q5NV69, P01782, Q5NV92, P01599, P01714, P01768, P06312, A2KUC3, A0A0C4DH73, P01715, P01706, P01780, P01721, Q5NV84, Q5NV62, P01701, P06310, P01705). Reactome uses a nested structure for complexes, which cannot be fully represented in SBML Level 3 Version 1 core
Derived from a Reactome Complex. Here is Reactomes nested structure for this complex: (P29353, P62993, Q07889, P52735, P19174, P42681, P42680, 16618, Q08881, Q9UKW4, P15498, Q06187, O43561, Q13094, P16885, O75791). Reactome uses a nested structure for complexes, which cannot be fully represented in SBML Level 3 Version 1 core
Derived from a Reactome Complex. Here is Reactomes nested structure for this complex: (16618, 16152, O15530). Reactome uses a nested structure for complexes, which cannot be fully represented in SBML Level 3 Version 1 core
Derived from a Reactome Complex. Here is Reactomes nested structure for this complex: (Q04206, P19838). Reactome uses a nested structure for complexes, which cannot be fully represented in SBML Level 3 Version 1 core
Derived from a Reactome Complex. Here is Reactomes nested structure for this complex: (Q04206, P25963, P19838). Reactome uses a nested structure for complexes, which cannot be fully represented in SBML Level 3 Version 1 core
Derived from a Reactome Complex. Here is Reactomes nested structure for this complex: (18035, Q04759, Q9UDY8, O95999, Q9BXL7). Reactome uses a nested structure for complexes, which cannot be fully represented in SBML Level 3 Version 1 core
Derived from a Reactome Complex. Here is Reactomes nested structure for this complex: (18035, Q9Y4K3, Q04759, O95999, Q9UDY8, Q9BXL7). Reactome uses a nested structure for complexes, which cannot be fully represented in SBML Level 3 Version 1 core
Derived from a Reactome SimpleEntity. This is a small compound
Derived from a Reactome DefinedSet. This is a list of alternative entities, any of which can perform the given function
Derived from a Reactome EntityWithAccessionedSequence. This is a protein
Derived from a Reactome SimpleEntity. This is a small compound
Derived from a Reactome Complex. Here is Reactomes nested structure for this complex: (18035, Q9Y4K3, Q04759, Q9UDY8, O95999, Q9BXL7). Reactome uses a nested structure for complexes, which cannot be fully represented in SBML Level 3 Version 1 core
Derived from a Reactome Complex. Here is Reactomes nested structure for this complex: (P29353, P63000, P62993, Q07889, 2xQ13177, P52735, P19174, 2xQ13153, 16618, Q9UKW4, P15498, 15996, O43561, Q13094, P16885, O75791). Reactome uses a nested structure for complexes, which cannot be fully represented in SBML Level 3 Version 1 core
Derived from a Reactome EntityWithAccessionedSequence. This is a protein
Derived from a Reactome Complex. Here is Reactomes nested structure for this complex: (P01116, P01112, P01116, 17552, P01111). Reactome uses a nested structure for complexes, which cannot be fully represented in SBML Level 3 Version 1 core
Derived from a Reactome EntityWithAccessionedSequence. This is a protein
Derived from a Reactome DefinedSet. This is a list of alternative entities, any of which can perform the given function
Derived from a Reactome DefinedSet. This is a list of alternative entities, any of which can perform the given function
Derived from a Reactome Complex. Here is Reactomes nested structure for this complex: (Q5NV64, P01615, Q5NV79, P01825, P01762, P01766, Q5NV61, P01817, A0A075B6S6, P01718, Q5NV81, P01772, P01834, P01709, A0A075B6P5, Q5NV91, P01824, P01699, Q5NV65, P01601, Q5NV68, P01854, P0DOY2, 2xP23083, P04432, P01593, P01814, Q5NV86, Q5NV83, P01767, Q5NV87, P01703, P0CG04, P01594, P01611, Q5NV75, P01624, Q5NV89, P06315, A2NXD2, P06331, P01763, A0M8Q6, P04433, P04430, P01597, P04211, Q5NV80, P01742, A2NJV5, P01704, Q5NV85, Q5NV90, Q5NV67, P01602, P0CF74, Q5NV82, P0DOY3, Q6PIL0, 6890, P01717, P80748, Q5NV66, P01619, P01743, P01764, P01700, A0A0C4DH25, P01614, Q5NV69, P01782, Q5NV92, P01599, P01714, P01768, P06312, A2KUC3, A0A0C4DH73, P01715, P01706, P01780, P01721, Q5NV84, Q5NV62, P01701, P06310, P01705). Reactome uses a nested structure for complexes, which cannot be fully represented in SBML Level 3 Version 1 core
Derived from a Reactome CandidateSet. A list of entities, one or more of which might perform the given function
Derived from a Reactome DefinedSet. This is a list of alternative entities, any of which can perform the given function
Derived from a Reactome EntityWithAccessionedSequence. This is a protein
Derived from a Reactome SimpleEntity. This is a small compound
Derived from a Reactome SimpleEntity. This is a small compound
Derived from a Reactome EntityWithAccessionedSequence. This is a protein
Derived from a Reactome Complex. Here is Reactomes nested structure for this complex: (18035, Q04759, Q9BXL7). Reactome uses a nested structure for complexes, which cannot be fully represented in SBML Level 3 Version 1 core
Derived from a Reactome DefinedSet. This is a list of alternative entities, any of which can perform the given function
Derived from a Reactome Complex. Here is Reactomes nested structure for this complex: (P29353, Q9UKW4, P15498, P62993, Q07889, P52735, P19174, O43561, Q13094, P16885, O75791). Reactome uses a nested structure for complexes, which cannot be fully represented in SBML Level 3 Version 1 core
Derived from a Reactome Complex. Here is Reactomes nested structure for this complex: (Q5NV64, P01615, Q5NV79, P01825, 2xP30273, P01762, P01766, Q5NV61, P01817, A0A075B6S6, P01718, Q5NV81, P01772, P01834, P01709, A0A075B6P5, Q5NV91, Q01362, P01824, P01699, Q5NV65, P01601, Q5NV68, P07948, P01854, P0DOY2, 2xP23083, P12319, P04432, P01593, P01814, Q5NV86, Q5NV83, P01767, Q5NV87, P01703, P0CG04, P01594, P01611, Q5NV75, P01624, Q5NV89, P06315, A2NXD2, P06331, P01763, A0M8Q6, P04433, P04430, P01597, P04211, Q5NV80, P01742, A2NJV5, P01704, Q5NV85, Q5NV90, Q5NV67, P01602, P0CF74, Q5NV82, P0DOY3, Q6PIL0, P01717, P80748, Q5NV66, P01619, P01743, P01764, P01700, A0A0C4DH25, P01614, Q5NV69, P01782, Q5NV92, P01599, P01714, P01768, P06312, A2KUC3, A0A0C4DH73, P01715, P01706, P01780, P01721, Q5NV84, Q5NV62, P01701, P06310, P01705). Reactome uses a nested structure for complexes, which cannot be fully represented in SBML Level 3 Version 1 core
Derived from a Reactome Complex. Here is Reactomes nested structure for this complex: (29105, 29034, Q08209, P63098, P16298). Reactome uses a nested structure for complexes, which cannot be fully represented in SBML Level 3 Version 1 core
Derived from a Reactome Complex. Here is Reactomes nested structure for this complex: (4xQ14571, 4xQ14643, 4xQ14573). Reactome uses a nested structure for complexes, which cannot be fully represented in SBML Level 3 Version 1 core
Derived from a Reactome DefinedSet. This is a list of alternative entities, any of which can perform the given function
Derived from a Reactome Complex. Here is Reactomes nested structure for this complex: (18035, Q04759, Q9BXL7). Reactome uses a nested structure for complexes, which cannot be fully represented in SBML Level 3 Version 1 core
Derived from a Reactome Complex. Here is Reactomes nested structure for this complex: (O00459, P27986, P42338, P42336). Reactome uses a nested structure for complexes, which cannot be fully represented in SBML Level 3 Version 1 core
T219, T538 at the activation loop, S676 at the turn motif and S695 at the hydrophobic motif are autophosphorylated in cis-maanner. Posphorylation of T538 is critical for kinase activation and it stabilises the open active conformation. Some studies suggest the involvement of PDK1 (3-phosphoinositide-dependent protein kinase 1) and GLK kinases in the phosphorylation T538.
MKK7 is activated by MEKK1 and the residues serine 271 and threonine 275 are the potential phosphorylation sites that are crucial for its kinase activity (phosphorylation sites are based on sequence alignment with MAP kinase kinase family members).
小君的bZIP域和安全系数形成一个x形-helical structure, which binds to the palindromic AP-1 site (TGAGTCA) (Glover and Harrison, 1995).
BCL10和MALT1蛋白质形成高分子重量t oligomers and only these oligomeric forms can activate IKK in vitro (Sun et al. 2004). BCL10 proteins form homo-oligomers through CARD-CARD interactions whereas in MALT1 the tandem Ig-like domains naturally form oligomers with a tendency towards dimers and tetramers (Dong et al. 2006, Quiu and Dhe-Paganon 2011). These CBM oligomers provides the molecular platform, which can facilitate dimerization or serve as scaffolds on which proteases and kinases involved in NF-kB activation are assembled and activated.
BTK/ITK are activated in a two step model. In the first step they are recruited to the membrane by binding to PIP3 or, alternatively with other binding partners like SLP-76. Once at the membrane SYK or Src-kinases in the vicinity phosphorylates Y551 (Y512 in ITK) in the activation loop of the catalytic domain of BTK to fully activate it (Rawlings et al. 1996, Park et al. 1996, Kawakami et al. 1994).
Phosphoinositol 4,5-bisphosphate (PIP2) is cleaved in to two most important second messengers diacylglycerol (DAG) and Inositol 1,4,5-triphosphate (IP3) by phospholipase C (PLC). DAG remains within the membrane and activates protein kinase C (PKC) while IP3 leaves the cell membrane and binds to IP3 receptor that releases Ca2+ from endoplasmic reticulum (ER).
FCERI is primarily expressed on mast cells and basophils as a tetrameric complex comprising an IgE-binding alpha subunit, a signal amplifying membrane-tetraspanning beta subunit, and a disulfide-linked gamma chain dimer that provides the receptor its signaling competence (Blank and Rivera 2004). In the absence of an antigen or allergen, FCERI receptor binds to monomeric IgE antibodies, and thus the receptor adopts the antigenic specificity of the prevalent IgE repertoire (Garman et al. 2000). Mast cell activation is initiated when multivalent antigen crosslinks the IgE bound to the high-affinity FCERI, thereby aggregating FCERI (Siraganian 2003). Antigen driven aggregation of FCERI then elicits intracellular signals that result in mast cell exocytosis.
Immunoglobulin-E (IgE)-mediated allergic responses require the binding of the IgE antibody to its high-affinity receptor, Fc epsilonRI (FCERI). Binding of one receptor blocks the binding of a second receptor. After this antigens can bind and crosslink IgE molecules held at the cell surface by FCERI (Garman et al. 2000).
在phosphorylation of the IKK beta, the regulatory subunit NEMO undergoes K-63-linked polyubiquitination. Ubiquitinated TRAF6 trimer, acts as a E3 ligase and induces this ubiquitination. The ubiquitin target sites in NEMO are not yet clearly identified. Studies of different NF-kB signaling pathways revealed several potential ubiquitination sites on NEMO (e.g., K285, K277, K309 and K399) (Fuminori et al. 2009).
FCERI aggregation has been shown to activate JNK as well as protein kinases upstream of JNK, such as MEKK1 (Mitogen-activated protein kinase/ERK Kinase Kinase-1) and JNK kinase (JNKK). PAK has been shown to be the upstream kinase involved in the activation of MEKK1, however no direct phosphorylation of MEKK1 by PAK is observed. Two threonine residues at positions 1400 and 1412 (analogous to 1381 and 1393 in mouse) in the activation loop of MEKK1 between the kinase subdomains VII and VIII are essential for its catalytic activity. The catalytic domain of MEKK1 is able to autophosphorylate these residues, enhancing its own activity.
This describes an Event/CatalystActivity that is positively regulated by the Regulator (e.g., allosteric activation)
PI3K activation results in recruitment of the serine/threonine kinase PDK1, (3-phosphoinositide-dependent kinase 1) to the plasma membrane where PDK1 subsequently phosphorylates and activates AKT. PDK1 with its PH domain binds to either PIP3 or PIP2 and is translocated to the plasma membrane. PDK1 seems to exist in an active, phosphorylated configuration under basal conditions (Vanhaesebroeck and Alessi 2000).
肥大细胞表达mem Tec的家庭bers (i.e. BTK, ITK, RLK and TEC) and are activated upon cross-linking of FCERI. They are recruited to the membrane via the interaction of their PH domain with PtdIns(3,4,5)P3 phosphate and their SH2 domain with Y145 of SLP-76 (Kettner et al. 2003). BTK is more important for early response such as phosphorylation of PLC-gamma2 and Ca2+ mobilization, whereas ITK regulates the late responses such as changes in gene expression and cytokine secretion. BTK deficient mice have mild defects in degranulation and severe impairments in the production of proinflammatory cytokines upon FCERI cross-linking (Hata et al. 1998). ITK deficient mice have been reported to have reduced MC degranulation and responses to allergic asthma (Forssell et al. 2005). However, Bone marrow derived mast cells (BMMC) derived from ITK deficient mice display a normal degranulation response but secrete elevated level of cytokines (TNFa and IL-13) (Iyer and August 2008). TEC kinase is also one of the crucial regulators of murine mast cell function. TEC is phosphorylated and activated upon FCERI stimulation. TEC deficient bone marrow derived mast cells did not show any in vitro or in vivo defects in histamine release. However, the generation of the leukotriene LTC4 was severely impaired in the absence of TEC (Schmidt et al. 2009).
PAK1 kinase is a member of serine/threonine protein kinase family and is widely believed as mediator between Cdc42 and Rac1 and the JNK signal transduction pathway. PAK1 is involved in regulating FCERI mediated mast cell degranulation via effects on calcium mobilisation and cytoskeletal changes (Allen et al. 2009). The conventional PAK family contains a N-terminal conserved Cdc42/Rac-interacting binding domain (CRIB) that overlaps a kinase inhibitory (KI) domain and a C-terminal catalytic domain. PAK1 molecules form trans-inhibited homodimers in which the N-terminal kinase inhibitory (KI) domain of one PAK1 molecule in the dimer binds and inhibits the C-terminal catalytic domain of the other. Isoprenylated Rac1/Cdc42-GTP localized to the membrane recruits PAK1 by binding to the N-terminal CRIB domain. Binding of activated Cdc42/Rac1, breaks the PAK1-dimer and removes the trans-inhibition and stimulates serine/threonine kinase activity of that allows autophosphorylation (Lu and Mayer 1999, Parrini et all. 2009, Zhao et al. 2005).
GRB2适配器蛋白质,其中包含一个中心SH2 domain flanked by N- and C-terminal SH3 domains. GRB2 acts downstream of receptor protein-tyrosine kinases and is involved in Ras and MAP kinase pathway activation by associating with the guanine exchange factor (GEF) SOS. GRB2 is constitutively bound to SOS through its SH3 domains, which interact with a proline-rich sequence in the C-terminal part of SOS (Chardin et al. 1993). Following phosphorylation of LAT, the GRB2:SOS complex binds to the phosphorylated tyrosines and is thereby translocated to the inner face of the plasma membrane where inactive RAS:GDP resides. The three distal tyrosines, Y171, Y191 and Y226 of LAT are responsible for GRB2 association (Balagopalan et al. 2010, Zhang et al. 2000).
Rac1 exists in inactive state in the cytosol until the reception of extracellular signals by the cell. To be functional Rac1 is rapidly targeted to the plasma membrane upon cell stimulation. The main factors involved in this mobilisation are the Rac GEFs like VAV and phospholipids (PtdIns(4,5)P2, PtdIns(3,4,5) P3) and lipid rafts at the plasma membrane. VAV catalyses the disassociation of GDP from Rac1 by modifying the nucleotide-binding site such that GDP is released and subsequently replaced. The incoming GTP occupies the nucleotide binding site and finally displaces VAV from Rac1 (Bos et al. 2007, Bustelo et al. 2012).
LAT palmitoylated和膜相关调整or protein. It rapidly becomes tyrosine-phosphorylated upon receptor engagement. LAT has nine conserved tyrosine residues of which five have been shown to undergo phosphorylation (Y127, Y132, Y171, Y191 and Y226). Src family kinases, SYK and ZAP-70 efficiently phosphorylate LAT on these tyrosine residues (Jiang and Cheng 2007, Paz et al. 2001). Phosphorylation of LAT creates binding sites for the Src homology 2 (SH2) domain proteins PLC-gamma1, GRB2 and GADS, which indirectly bind SOS, VAV, SLP-76 and ITK (Wange 2000).
GRB2-bound SOS promotes the formation of active GTP-bound RAS. This activates the mitogen-activated protein kinase (MAPK) cascade, leading to cell growth and differentiation.
GRB2适配器蛋白质,其中包含一个中心SH2 domain flanked by N- and C-terminal SH3 domains. GRB2 acts downstream of receptor protein-tyrosine kinases and is involved in Ras and MAP kinase pathway activation by associating with the guanine exchange factor (GEF) SOS. GRB2 is constitutively bound to SOS through its SH3 domains, which interact with a proline-rich sequence in the C-terminal part of SOS (Chardin et al. 1993). GRB2-SOS complex binds to phosphotyrosine Y239 and Y317 of SHC1. SHC1 associates with the tyrosine-phosphorylated ITAMs of the FCERI beta-chain and can recruit SOS to membrane. SHC1 and SOS have also been described to associate with LAT via GRB2. Shc binding to Phospho-ITAMs (in vitro binding to phospho peptides) has never been linked to any biological function (activation) and is probably not relevant in a physiological setting.
Tyrosine phosphorylated ITAM in FCERI gamma subunit serves as docking site for SYK (spleen tyrosine kinases), whereas the beta-subunit ITAM has an extra tyrosine and is shorter than canonical ITAM which makes it unfit to bind SYK. Association of SYK to FCERI gamma-subunit disrupts the COOH-terminal-SH2 interdomain interaction of SYK causing a conformational change opening the molecule leading to its activation (Siraganian et al. 2010, de Castro et al. 2010).
Activated human JNK kinases (MKK4 and MKK7) phosphorylate Thr183 and Tyr185 residues in the characteristic Thr-Pro-Tyr phosphoacceptor loop of each JNK. JNK is differentially regulated by MKK4 and MKK7 depending on the stimulus. MKK7 is the primary activator of JNK in TNF, LPS, and PGN responses. However, TLR3 cascade requires both MKK4 and MKK7. Some studies reported that in three JNK isoforms tested MKK4 shows a striking preference for the tyrosine residue (Tyr-185), and MKK7 a striking preference for the threonine residue (Thr-183).
泛素化后NF-kappa-B抑制剂alpha (NFKBIA or IκBα) is rapidly degraded by 26S-proteasome, allowing NF-kB to translocate into the nucleus where it activates gene transcription (Spencer et al. 1999).Severe acute respiratory syndrome coronavirus (SARS-CoV) 1a-encoded papain-like protease (PLPro or nsp3) was found to cleave Lys48-linked polyUb chains of NFKBIA (IκBα) (Békés M et al. 2016;Ratia K et al. 2014) suggesting an inhibitory effect of SARS-CoV-1 nsp3 on 26S proteasome-dependent degradation of NFKBIA.
k - 63与polyubiquitin TRAF6 pro(酒吧)链vides a scaffold to recruit downstream effector molecules to activate NF-kB. Transforming growth factor beta-activated kinase 1 (TAK1) is a member of the mitogen-activated protein kinase (MAPK) kinase kinase family is shown to be an essential intermediate that transmits the upstream signals from the receptor complex to the downstream MAPKs and to the NF-kB pathway (Broglie et al. 2009). TAK1-binding protein 1 (TAB1), TAB2 and TAB3 constitutively bound to TAK1. TAB1 acts as the activation subunit of the TAK1 complex, aiding in the autophosphorylation of TAK1, whereas TAB2 and its homologue TAB3, act as a adaptors of TAK1 that facilitate the assembly of TAK1 complex to TRAF6. The highly conserved C-terminal zinc finger domain of TAB2 and TAB3 binds preferentially to the K-63-linked polyubiquitin chains on TRAF6 (Broglie et al. 2009, Besse et al. 2007).
DAG along with intracellular calcium signals cooperatively to activate PKCs, which then trigger other pathways such as the NF-kB pathway, ultimately leading to mast cell (MC) degranulation and cytokine production (Wu 2011). PKC theta is a member of the Ca++ independent and DAG dependent, novel PKC subfamily expressed mainly in T cells. It contains, N-term C2 like domain, a pseudosubstrate (PS), DAG binding (C1) domain and a C-term kinase domain. The PS sequence resembles an ideal substrate with the exception that it contains an alanine residue instead of a substrate serine residue, is bound to the kinase domain in the resting state. As a result, PKC theta is maintained in a closed inactive state, which is inaccessible to cellular substrates.MCs express several Protein kinase C (PKC) isozymes and these kinases are involved in both the activation and termination of the degranulation process. PKC-delta is a negative regulator of FCERI mediated mast cell degranulation, whereas PKC-theta facilitates in degranulation (Leitges et al. 2002, Liu et al. 2001). In response to FCERI activation PKC-theta translocates to membrane by binding to DAG with its C1 domain. PKC-theta exists in two conformations closed/inactive and open/active state. In resting state, PKC-theta is autoinhibited where the pseudosubstrate sequence in the N-terminal regulatory region of PKC-theta forms intramolecular interaction with the substrate-binding region in the catalytic domain. This prevents the catalytic domain gaining access to substrates. The allosteric change of PKC-theta from closed to open state involves two important mechanisms: DAG binding to the C1 domains and autophosphorylation of T538 on the activation loop. Interaction with DAG induces conformational change resulting in the exposure of the activation loop of PKC-theta (Wang et al. 2012, Melowic et al. 2007).
Binding of TAB2 and TAB3 to K63-linked polyubiquitin chains leads to the activation of TAK1 by an uncertain mechanism. Phosphorylation of TAK1 within the activation loop of the kinase is absolutely required for TAK1 activity. TAB1 is known to augment TAK1 catalytic activity by mediating spontaneous oligomerization and induces autophosphorylation of TAK1 (Kishimoto et al. 2000). The binding of TAB2/3 to polyubiquitinated TRAF6 may facilitate polyubiquitination of TAB2/3 by TRAF6 (Ishitani et al. 2003), which might result in conformational changes within the TAK1 complex that leads to the activation of TAK1. Some biochemical studies revealed that free K63 polyubiquitin chains, which are not conjugated to any cellular protein, can directly activate the TAK1 kinase complex (Xia et al. 2009).
Phosphorylated Y452, Y476, and Y584 of GAB2 binds p85 regulatory subunit of PI3K kinase, resulting in activation of PI3K pathway. PI3K is required for mast cell degranulation and anaphylaxis response but not for cytokine production or contact hypersensitivity (Nishida et al. 2011). Activated PI3K generates second messenger PtdInsP3 (PIP3) at the inner membrane, which provides docking sites for pleckstrin homology (PH) domains of PDK1, AKT and BTK. Activated AKT controls major downstream targets like mTORC1, FOXO3 and GSK3beta pathways that regulate mast cell growth, homeostasis, and cytokine production. BTK triggers PLCgamma2 activation, thereby inducing activation of the transcription factor NFAT and NF-kB.
SHC is an adapter protein that has been implicated in Ras activation. Mast cells express two isoforms of 46 and 52 kDa. Both isoforms of SHC have two domains, an N-terminal phosphotyrosine-binding (PTB) domain and a C-terminal SH2 domain that allows Shc to bind to proteins containing phosphorylated tyrosine residues. Following receptor stimulation, SHC is phosphorylated by Src kinases Syk on Y239, Y240 and Y317 (p56 isoform). Both phosphotyrosines Y239 and Y317 creates the binding site for the SH2 domain of GRB2.
Nuclear factor of activated T-cells (NFAT) is a transcription factor which induces genes responsible for cytokine production, for cell-cell interactions etc. NFAT transcription activity is modulated by calcium and Calcineurin concentration. In resting cells NFAT is phosphorylated and resides in the cytoplasm. Phosphorylation sites are located in NFAT's regulatory domain in three different serine rich motifs, termed SRR1, SP2 and SP. Upon stimulation, these serine residues are dephosphorylated by calcineurin, that thought to cause exposure of nuclear localization signal sequences triggering translocation of the dephosphorylated NFAT-CaN complex to the nucleus. Among all the phosphorylation sites one of the site in SRR-2 motif is not susceptable to dephosphorylation by CaN (Takeuchi et al. 2007, Hogan et al. 2003).
Ras guanyl nucleotide-releasing proteins (RasGRPs) are guanyl nucleotide exchange factors (GEFs) that activate Ras ultimately leading to MAPK activation. RasGRPs have a catalytic domain composed of Ras exchange motif (REM) and a CDC25 domain, an atypical pair of EF hands that bind calcium and a DAG-binding C1 domain. After PIP2 hydrolysis, RasGRPs are recruited to the plasma membrane by binding to DAG and calcium (Stone 2011, Liu et al. 2007). Upon T-cell activation RasGRP1 specifically interacts with and activates Ras on Golgi instead of the plasma membrane (Bivona et al. 2003). It remains to be determined whether activation of N-Ras by RasGRP1 in mast cells occurs in the Golgi or the plasma membrane (Liu et al. 2007). RasGRP4 is mast cell specific and is involved in the controls Ras activation.
Upon increase in calcium concentration, calmodulin (CaM) is activated by binding to four calcium ions (Crouch and Klee 1980).
Two major signaling steps are required for the removal of IkappaB (IkB) alpha an inhibitor of NF-kB: activation of the IkB kinase (IKK) and degradation of the phosphorylated IkB alpha. IKK activation and IkB degradation involve different ubiquitination modes; the former is mediated by K63-ubiquitination and the later by K48-ubiquitination. Mutational analysis of IkB alpha has indicated that K21 and K22 are the primary sites for addition of multiubiquitination chains while K38 and K47 are the secondary sites. In a transesterification reaction the ubiquitin is transferred from the ubiquitin-activating enzyme (E1) to an E2 ubiquitin-conjugating enzyme, which may, in turn, transfer the ubiquitin to an E3 ubiquitin protein ligase. UBE2D2 (UBC4) or UBE2D1 (UBCH5) or CDC34 (UBC3) acts as the E2 and SCF (SKP1-CUL1-F-box)-beta-TRCP complex acts as the E3 ubiquitin ligase (Strack et al. 2000, Wu et al. 2010). beta-TRCP (beta-transducin repeats-containing protein) is the substrate recognition subunit for the SCF-beta-TRCP E3 ubiquitin ligase. beta-TRCP binds specifically to phosphorylated IkB alpha and recruits it to the SCF complex, allowing the associated E2, such as UBC4 and or UBCH5 to ubiquitinate Ikappa B alpha (Baldi et al. 1996, Rodriguez et al. 1996, Scherer et al. 1995, Alkalay et al. 1995).
LYN localized in lipid rafts undergoes an intermolecular autophosphorylation at tyrosine 396. This residue is present in the activation loop, and its phosphorylation promotes LYN kinase activity.
Raft localized PKC-theta is phosphorylated and is activated. Phosphorylation of both tyrosine and serine-threonine residues is important in the regulation of PKC function. Six phosphorylation sites have been identified on PKC-theta: Y90, T219, T538, S676, S685, and S695. Phosphorylation of Y90 positively regulates NF-AT and NF-kB activation in T-cells. In mast cells Src family members Src and LYN have been shown to be involved in phosphorylating Y90 (Wang et al. 2012, Liu et al. 2001).
Dephosphorylated NFAT-calcineurin (CaN) complex translocates to nucleus, where it activates transcription of several cytokine genes (e.g..IL2).
TRAF6 is a ubiquitin ligase that plays a central role in the IKK-dependent canonical NF-kB pathway. It is recruited to the CBM complex by binding to MALT1. The MALT1 C-terminal Ig domain and extension contain two binding motifs for TRAF6 (Noels et al 2007). After oligomerzation TRAF6, together with Ubc13/Uev1A, activates TAK1 and IKK. It also acts as an E3 ligase for MALT1 and mediates lysine 63-linked ubiquitination (Oeckinghaus et al. 2007).
The released NF-kB transcription factor (p50/p65) with unmasked nuclear localization signal (NLS) moves in to the nucleus. Once in the nucleus, NF-kB binds DNA and regulate the expression of genes encoding cytokines, cytokine receptors, and apoptotic regulators.
磷酸化的变风量空调刺激GEF活动for RAC1, and thus it plays an important role in linking FCERI to the RAC1-JNK pathway. VAV exists in an auto-inhibitory state, folded in such a way as to inhibit the GEF activity of its DH domain. This folding is mediated through binding of tyrosines in the acidic domain to the DH domain and through binding of the calponin homology (CH) domain to the C1 region. Activation of VAV may involve three events which relieve this auto-inhibition: phosphorylation of tyrosines in the acidic domain causes them to be displaced from the DH domain; binding of a ligand to the CH domain may cause it to release the C1 domain; binding of the PI3K product PIP3 to the PH domain may alter its conformation (Aghazadeh et al. 2000). VAV is phosphorylated on tyrosine residue (Y174 in VAV1/172 in VAV2/173 in VAV3) in the acidic domain. This is mediated by SYK and Src-family tyrosine kinases (Deckert et al. 1996, Schuebel et al. 1998). Once activated, VAV is involved in the activation of RAC1, PAK1, MEK and ERK and cytokine production.
This describes an Event/CatalystActivity that is positively regulated by the Regulator (e.g., allosteric activation)
在人类中,IkB激酶(IKK)复杂的作为the master regulator for the activation of NF-kB by various stimuli. It contains two catalytic subunits, IKK alpha and IKK beta, and a regulatory subunit, IKKgamma/NEMO. The activation of IKK complex is dependent on the phosphorylation of IKK alpha/beta at its activation loop and the K63-linked ubiquitination of NEMO. This basic trimolecular complex is referred to as the IKK complex. IKK subunits have a N-term kinase domain a leucine zipper (LZ) motifs, a helix-loop-helix (HLH) and a C-ter NEMO binding domain (NBD). IKK catalytic subunits are dimerized through their LZ motifs. IKK beta is the major IKK catalytic subunit for NF-kB activation. Activated TAK1 phosphorylate IKK beta on S177 and S181 (S176 and S180 in IKK alpha) in the activation loop and thus activate the IKK kinase activity, leading to the IkB alpha phosphorylation and NF-kB activation.
CARMA1 phosphorylation initiates its oligomerization and the coiled-coil (CC) domain of CARMA1 is hypothesized to mediate this clustering (Tanner et al. 2007).
TRAF6 possesses ubiquitin ligase activity and undergoes K-63-linked auto-ubiquitination after its oligomerization. In the first step, ubiquitin is activated by an E1 ubiquitin activating enzyme. The activated ubiquitin is transferred to a E2 conjugating enzyme (a heterodimer of proteins Ubc13 and Uev1A) forming the E2-Ub thioester. Finally, in the presence of ubiquitin-protein ligase E3 (TRAF6, a RING-domain E3), ubiquitin is attached to the target protein (TRAF6 on residue Lysine 124) through an isopeptide bond between the C-terminus of ubiquitin and the epsilon-amino group of a lysine residue in the target protein. In contrast to K-48-linked ubiquitination that leads to the proteosomal degradation of the target protein, K-63-linked polyubiquitin chains act as a scaffold to assemble protein kinase complexes and mediate their activation through proteosome-independent mechanisms. This K63 polyubiquitinated TRAF6 activates the TAK1 kinase complex.
Upon phosphorylation NATL/LAT2 recruits GRB2:SOS complex into the receptor-signaling complex. Residues Y95, Y118, Y136, Y193, Y233 are the putative GRB2-binding sites on NTAL (Iwaki et al. 2007).
NTAL cooperates with LAT in mast cells to activate PI3K pathway and cytokine production through Grb2-associated binding protein 2 (GAB2) (Gonzalez-Espinosa et al. 2003). FCERI aggregation induced translocation of a significant fraction of GAB2 from the cytosol to the plasma membrane by binding GRB2. Two of the proline-rich motifs in GAB2 are binding sites for the SH3 of GRB2. GAB2 is also recruited to plasma membrane by binding to phosphatidylinositol-3,4,5-trisphosphate (PIP3) with its plecstrin homology (PH) domain. GAB2 can be recruited to FCERI indirectly through GRB2 bound SHC1. SHC1 is recruited to the FCERI beta chain through its SH2 domain and becomes tyrosyl-phosphorylated. Phosphorylated SHC provides a docking site for the GRB2 and this in turn recruits GAB2 (Yu et al. 2006). GAB2 and PI3K are required for FCERI-induced granule translocation.
当绑定到的高亲和性IgE受体(fcI), IgE acts as an environmental sensor that detects allergens and induces allergic responses from the cell's interior. Omalizumab is a monoclonal antibody that binds free IgE preventing it from binding to FCERI. Moreover, reduction of free IgE concentrations reduce FCERI expression level. Omalizumab is approved for the treatment of patients with severe allergic asthma. Use of omalizumab is associated with several side effects, including injection site reactions, viral and upper respiratory tract infections, headache, sinusitis, and pharyngitis. The main severe adverse effect is anaphylactic shock, with a rate of occurrence of 1 to 2 patients per 1,000 (Davydov 2005, Arm et al. 2014).
Tyrosine phosphorylation of PLC-gamma enhances its catalytic activity. BTK and SYK are involved in the phosphorylation of PLC-gamma (PLCG). Phosphorylation of tyrosine residues 753, 759, 1197, and 1217 in PLCG2 and 771, 783, and 1254 in PLCG1 have been identified as BTK/SYK-dependent phosphorylation sites.
NF-kB is sequestered in the cytosol of unstimulated cells through the interactions with a class of inhibitor proteins, called IkBs, which mask the nuclear localization signal (NLS) of NF-kB and prevent its nuclear translocation. A key event in NF-kB activation involves phosphorylation of IkB (at sites equivalent to Ser32 and Ser36 of IkB-alpha or Ser19 and Ser22 of IkB-beta) by IKK. The phosphorylated IkB-alpha is recognized by the E3 ligase complex and targeted for ubiquitin-mediated proteasomal degradation, releasing the NF-kB dimer p50/p65 into the nucleus to turn on target genes. (Karin and Ben-Neriah 2000)
的磷脂酶PLC-gamma是一个重要的mediator of TCR, FCERI and DAP12 signal transduction. PLC-gamma hydrolyzes phosphatidylinositol 4,5-bisphosphate (PIP2) to produce inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG) and in-turn promotes the Ca+2 influx and activation of NFAT. Activation of PLC-gamma1 entails the binding of PLC-gamma1 to both LAT and SLP-76 adapter proteins. The amino-terminal SH2 domain of PLC-gamma1 was shown to preferentially bind phosphorylated LAT Y132 with high affinity and no detectable binding to phosphorylated tyrosines 171, 191, and 226. PLC-gamma1 was also shown to bind the adapter protein SLP-76 indirectly through GADS, which is bound to LAT at Y171 and Y191. SH3 domain of PLC-gamma1 associates with the proline-rich region of SLP-76 (Yablonski et al. 2001). PLC-gamma1 associates with Gads/SLP-76 complex before binding to p-Y132 of LAT (Houtman et al. 2005). PLC-gamma1 association with LAT is stabilized by Gads/SLP-76 bound to LAT (Zhu et al.2003). Association of PLC-gamma to LAT and SLP-76 couples it to the kinases (Syk and Tec family kinase) required for tyrosine phosphorylation and activation of PLC-gamma. Mast cells express both PLC-gamma1 and PLC-gamma2 isoforms, which are phosphorylated by BTK/ITK and/or SYK. FCERI-dependent Ca2+ release requires the recruitment of PLC-gamma by SLP-76 and LAT. In mast cells, increased intracellular calcium triggers rapid release of preformed mediators, through a process of vesicle exocytosis, known as degranulation.Recruitment and activation of phospholipase C gamma (PLC-gamma) is involved in DAP12 signal transduction. Phosphorylation of multiple substrates including PLC-gamma1 has been observed in Ly49D/DAP12 triggered NK cells (McVicar et al. 1998). In myeloid cells, PLC-gamma2 is recruited and then phosphorylated upon activation of TREM2 and DAP12 (Peng et al. 2010).
Upon dimer disassociation PAK1 autophosphorylates in both cis- and trans- manner. Serine 144 (S144) in the GTPase-binding domain and threonine 423 (T423) in the activation loop are the target sites for autophosphorylation (Parrini et al. 2002).
c-Jun NH2 terminal kinase (JNK) plays a role in conveying signals from the cytosol to the nucleus, where they associate and activate their target transcription factors.
The Fos proteins(c-Fos, FosB, Fra1 and Fra2), which cannot homodimerize, form stable heterodimers with Jun proteins and thereby enhance their DNA binding activity. On activation of the MAPK pathway, Ser-374 of Fos is phosphorylated by ERK1/2 and Ser-362 is phosphorylated by RSK1/2, the latter kinases being activated by ERK1/2. If stimulation of the MAPK pathway is sufficiently sustained, ERK1/2 can dock on an upstream FTYP amino acid motif, called the DEF domain (docking site for ERKs, FXFP), and phosphorylate Thr-331 and Thr-325.Phosphorylation at specific sites enhances the transactivating potential of several AP-1 proteins, including Jun and Fos, without having any effect on their DNA binding activities. Thus, phosphorylation of Ser-362 and Ser-374 stabilizes c-Fos but has no demonstrated role in the control of transcriptional activity. On the contrary, phosphorylation of Thr-325 and Thr-331 enhances c-Fos transcriptional activity but has no demonstrated effect on protein turnover.
VAV an activator of RAC-GTPases, is redistributed to plasma membrane and is phosphorylated following engagement of FCERI. Phosphorylated SLP-76 tyrosines Y113 and Y128 (112Y and 128Y in mouse) provide binding sites for the SH2 domains of VAV. The binding of VAV to these phosphotyrosine residues may link SLP-76 to the Jun amino-terminal kinase (JNK) pathway and the actin cytoskeleton (Kettner et al. 2003).In addition to its known role as guanine nucleotide exchange factor (GEF), VAV also modulates cytokine production in mast cells. VAV1-deficient bone marrow-derived mast cells exhibited reduced degranulation and cytokine production and calcium release in addition of reduced activation of c-Jun NH2-terminal kinase 1 (JNK1), although tyrosine phosphorylation of FCERI, SYK and LAT was normal (Manetz et al. 2001, Arudchandran et al. 2000, Song et al. 1999).
GAB2 have multiple tyrosyl phosphorylation sites that are phosphorylated up on activation of FCERI. SYK is the major tyrosine kinase involved in GAB2 phosphorylation. FYN is also shown to contribute to GAB2 tyrosyl phosphorylation but it is not clear whether GAB2 is a direct substrate of FYN (Yu et al. 2006, Parravicini et al. 2002). GAB2 tyrosines (Y452, Y476 and Y584) in the YXXM motif can be the target phosphorylation sites for SYK/FYN kinases (Chan et al. 2010, Harir et al. 2007).
Gads/GRAP2 (GRB2-related adapter protein 2) is member of the GRB2 adaptor family with a central SH2 domain and linker region flanked by amino- and carboxy-terminal SH3 domains. SLP-76 associates constitutively via its central 20-amino acid proline-rich domain with the C-terminal SH3 domain of Gads, which recruits it to LAT following receptor stimulation. Upon LAT phosphorylation, Gads:SLP-76 complex principally binds to phosphorylated LAT tyrosine 191, with a reduced amount of binding to phosphorylated tyrosine 171 and no interaction with phosphorylated tyrosines 132 or 226 (Houtman et al. 2004, Zhu et al. 2003). Gads may promote cross-talk between the LAT and SLP-76 signaling complexes, thereby coupling membrane-proximal events to downstream signaling pathways (Liu et al. 1999). The LAT-Gads-SLP-76 complex creates a platform for the recruitment of multiple signaling molecules, including PLCgamma1, GRB2, NCK, Rho GEFs, VAV and the Tec-family kinases ITK and BTK (Liu et al. 1999 and 2001, Asada et al. 1999, Yablonski et al. 2001).
IP3 promotes the release of intracellular calcium.
This describes an Event/CatalystActivity that is positively regulated by the Regulator (e.g., allosteric activation)
This describes an Event/CatalystActivity that is negatively regulated by the Regulator (e.g., allosteric inhibition, competitive inhibition
Calcineurin (CaN), also called protein phosphatase 2B (PP2B), is a calcium/Calmodulin (CaM)-dependent serine/threonine protein phosphatase. It exists as a heterodimer consisting of CaM-binding catalytic subunit CaN A chain and a Ca+2 binding regulatory CaN B chain. At low calcium concentrations, CaN exists in an inactive state, where the autoinhibitory domain (AID) binds to the active-site cleft. Upon an increase in calcium concentration CaM binds to Ca+2 ions and gets activated. Active CaM binds to CaN regulatory domain (RD) and this causes release of the AID and activation of the phosphatase (Rumi-Masante et al. 2012). Binding of calcium to CaN B regulatory chain also causes a conformational change of the RD of CaN A chain (Yang and Klee 2000).
Activated MEKK1 then phosphorylates and activates SAPK/Erk kinase (SEK1), also known as MKK4 or Jun kinase kinase (JNKK) on serine and threonine residues at positions 257 and 261, respectively.
BCL10-MALT1 oligomers bind to TRAF6 and this in turn promotes the oligomerization of TRAF6 and activates its E3 ligase activity (Sun et al. 2004).
CARMA1 (CARD11/Caspase recruitment domain-containing protein 11), BCL10 (B-cell lymphoma/leukemia 10) and MALT1 (Mucosa-associated lymphoid tissue lymphoma translocation protein 1)/paracaspase have been identified as signaling components that act downstream of PKC-theta. CARMA1 is a scaffold protein and recruits BCL10, MALT1, PKC and TRAF6 to form a multi protein complex. CARMA1 exists in an inactive conformation in which the linker region binds to and blocks the accessibility of the CARD motif. Upon stimulation S552 and S645 linker residues are phosphorylated by PKC-theta and this may weaken this interaction, inducing an open conformation of CARMA1. Further phosphorylation studies have revealed other phosphorylation sites (S109, S551 and S555) that may also promote activation of CARMA1. Serene/threonine kinases PKC-beta, IKKbeta, HPK1 and CaMKII are involved in triggering CARMA1 activation (Thome et al. 2010, Rueda and Thome 2005). (only phosphorylated S552 and S645 are represented in this reaction)
The IP3 receptor (IP3R) is an IP3-gated calcium channel. It is a large, homotetrameric protein, similar to other calcium channel proteins such as ryanodine. The four subunits form a 'four-leafed clover' structure arranged around the central calcium channel. Binding of ligands such as IP3 results in conformational changes in the receptor's structure that leads to channel opening.
JNK (c-Jun N-terminal Kinase) phosphorylates several transcription factors including c-Jun after translocation to the nucleus.
Upon FCGRI-IgE aggregation, LYN kinase phosphorylates the tyrosine residues within the ITAM (immunoreceptor tyrosine-based activation motifs) of both the beta and gamma subunits. The detailed mechanism of the initial engagement of LYN kinase and FCERI is incompletely understood, but two different models have been proposed. One model postulates that a small fraction of LYN is constitutively bound to beta subunit of FCERI prior to activation. Aggregation of FCERI facilitates the transphosphorylation of one FCERI by LYN bound to a juxtaposed receptor (Vonakis et al. 1997, Draber and Draberova 2002). Alternative model postulates that LYN is observed in lipid rafts enriched in glycosphingolipids, cholesterol, and glycosylphosphatidylinositol-anchored proteins and upon aggregation, FCERI rapidly translocates into lipid rafts, where it is phosphorylated by LYN kinase. Either the association of LYN or FCERI or both with lipid rafts is important for initiating this phosphorylation process (Young et al. 2003, Kovarova et al. 2002, Draber and Draberova 2002).Beta subunit ITAM differs from canonical ITAMs in two ways; the spacing between the two canonical tyrosines harbours a third tyrosine, and it is one amino acid shorter than in canonical ITAMs, thus making it unfit to bind and recruit Syk. Among the three tyrosine residues (Y219, Y225 and Y229), Y219 may play a predominant role in beta chain function and LYN recruitment. Mutation of this tyrosine would decrease substantially LYN association and subsequent phosphorylation of Y225 and Y229. This would result in decreased gamma phosphorylation and decreased SYK recruitment and activation (On et al. 2004).
假定NTAL和LAT发挥互补作用ive regulation of FCERI-mediated degranulation. Upon FCERI aggregation NTAL is phosphorylated by LYN, SYK and KIT on different tyrosines. Phosphorylated NTAL likely contributes to the activation of mast cells by providing docking sites for the recruitment of critical signaling molecules into the lipid raft. There are about ten tyrosines in LAT2 of which five tyrosines principally phosphorylated by SYK are recognised as putative GRB2-binding sites, being part of a YXN motif, whereas LYN and KIT phosphorylate both tyrosines contained in the YXN motifs as well as tyrosines outside of the YXN motifs (Iwaki et al. 2008).
PI3K catalyzes the conversion of phosphatidylinositol 4,5-bisphosphate (PIP2) to phosphatidylinositol-3,4,5-triphosphate (PIP3). This PIP3 acts as a membrane anchor for the downstream proteins like PDK1 and AKT.
Multiple sites of phosphorylation are known to exist in SYK, which both regulate its activity and also serve as docking sites for other proteins. Some of these sites include Y131 of interdomain A, Y323, Y348, and Y352 of interdomain B, and Y525 and Y526 within the activation loop of the kinase domain and Y630 in the C-terminus (Zhang et al. 2002, Lupher et al. 1998, Furlong et al. 1997). Phosphorylation of these tyrosine residues disrupts autoinhibitory interactions and results in kinase activation even in the absence of phosphorylated ITAM tyrosines (Tsang et al. 2008). SYK is primarily phosphorylated by Src family kinases and this acts as an initiating trigger by generating few molecules of activated SYK which are then involved in major SYK autophosphorylation (Hillal et al. 1997).
的磷酸化CARMA1引起构象change such that its CARD motif is exposed and is free to interact with BCL10 CARD motif. BCL10 constitutively associated with MALT1 and exists as a preformed complex in the cytoplasm. BCL10 and MALT1 have been identified as key positive regulators of FCERI-dependent NF-kB activation (Klemm et al. 2006). The resulting CARMA1-BCL10-MALT1 (CBM) complex may be stabilized by interactions between the CARMA1 coiled coil (CC) domain and a C-terminal MALT1 region that lacks the DD and first two Ig domains (Thome et al. 2010, Che et al. 2004). The CBM complex transmits activating signals that ultimately result in ubiquitination (Ub) and degradation of the NF-kB inhibitor, IkBa.
After initial phosphorylation by SFK's, subsequently Y223 (Y180 in ITK and Y206 in TEC) in the SH3 domain of BTK is autophosphorylated, which may prevent inhibitory intramolecular interactions (Nore et al. 2003, Joseph et al. 2007, Park et al. 1996)
SLP-76 lacks intrinsic catalytic activity and acts as a scaffold, recruiting other proteins for correct localization during molecular signal transduction (Bogin et al. 2007). Activation of FCERI leads to tyrosine phosphorylation of SLP-76 (Gross et al. 1999). SLP-76 has three potential tyrosine phosphorylation sites within its amino terminus region: Y113, Y128, and Y145. Phosphorylation may be mediated by SYK, analogous to the role of ZAP-70 in phosphorylating T-cell SLP-76 (Bubeck-Wardenberg et al. 1996).