BioPAX通路从转换“CLIP3和CYLD结合TNF信号传导复合物”在Reactome数据库。 左到右 CLIP3和CYLD结合TNF信号复合物 CAP-GLY含连接蛋白3（CLIP3或CLIPR-59）结构域被认为是功能的衔接蛋白招募CYLD到TNFR1信号，以方便在TNFα的RIPK1的CYLD介导的去泛素化信令（藤仓d等人2012）。RIPK1的CLIP3辅助CYLD介导的K63去泛素化可促进胱天蛋白酶8活化通过TNFα的诱导细胞凋亡。对细胞凋亡的诱导的TNFαCLIPR-59敲除的效果比在人更有效在人宫颈癌HeLa细胞肺泡基底上皮A549细胞或人纤维肉瘤HT1080细胞。这些结果表明，CLIPR-59的对TNF-α诱导的和RIP1介导的促凋亡信号是依赖于细胞类型和方面的作用（藤仓d等人2012）。 著作：Shamovsky，婆婆纳，2015年5月12日 审查：Gillespie，Marc E，2015-03-11 来自：Wajant，哈拉尔，2015年8月25日 编辑：Shamovsky，V，2015-02-15 tnf: TNFR1: TRADD: K63polyUb-RIPK1: BIRC2, 3、4 反应DB_ID：5357756 等离子体膜 基因本体论 去:0005886 K63polyUB-RIPK1 K63pUb-K377-RIP1 受体相互作用蛋白1 反应DB_ID：5212672 胞质 基因本体论 去：0005829. UniProt: Q13546 RIPK1 RIPK1 把 RIP1 FUNCTION丝氨酸 - 苏氨酸激酶，其是TNF介导的细胞凋亡，坏死的和炎症途径的关键调节物（PUBMED：31827280，PUBMED：31827281）。展品激酶活性依赖性功能调节细胞死亡和非激酶依赖支架功能调控炎症信号传导和细胞存活（PUBMED：11101870，PUBMED：19524512，PUBMED：19524513，PUBMED：29440439，PUBMED：30988283）。已经激酶依赖支架功能：在对TNFR1 TNF结合，RIPK1被募集到TNFR1信号复合物（TNF-RSC也称为复合物I），其中它充当一个支架蛋白促进细胞存活，部分地，通过激活经典的NF-κ-乙途径（通过相似性）。激酶活性是必不可少的，以调节性坏死和细胞凋亡，细胞死亡的两个平行的形式：在它的蛋白激酶活性的激活，调节的组件2死亡诱导复合物，即复合物IIA（RIPK1-FADD-CASP8），该驱动器的细胞凋亡，和复IIB（RIPK1-RIPK3-MLKL），该驱动器坏死的（通过相似性）。RIPK1需要限制CASP8依赖性TNFR1诱导的细胞凋亡（由相似性）。在正常条件下，RIPK1充当RIPK3依赖性坏死的抑制剂，通过复杂的IIB，其通过ZBP1诱导后催化MLKL的磷酸化RIPK3成分介导的过程（PUBMED：19524512，PUBMED：19524513，PUBMED：29440439，PUBMED：30988283）。经由CASP8的FADD介导的募集，其裂解RIPK1并限制TNF诱导坏死的抑制RIPK3介导性坏死（：19524512，PUBMED：19524513，PUBMED：PUBMED 29440439，PUBMED：30988283）。需要胚胎发育过程中抑制细胞凋亡和坏死的：通过防止与FADD从而限制CASP8的异常活化（通过相似性）TRADD的相互作用行为。 In addition to apoptosis and necroptosis, also involved in inflammatory response by promoting transcriptional production of pro-inflammatory cytokines, such as interleukin-6 (IL6) (PubMed:31827280, PubMed:31827281). Phosphorylates RIPK3: RIPK1 and RIPK3 undergo reciprocal auto- and trans-phosphorylation (PubMed:19524513). Phosphorylates DAB2IP at 'Ser-728' in a TNF-alpha-dependent manner, and thereby activates the MAP3K5-JNK apoptotic cascade (PubMed:17389591). Required for ZBP1-induced NF-kappa-B activation in response to DNA damage (By similarity).ACTIVITY REGULATION Serine-threonine kinase activity is inhibited by linear polyubiquitination ('Met-1'-linked) by the LUBAC complex (By similarity). Inhibited by necrostatins, including necrostatin-1, necrostatin-3 and necrostatin-4 (PubMed:23473668).SUBUNIT Homodimer (PubMed:29440439, PubMed:29681455). Interacts (via RIP homotypic interaction motif) with RIPK3 (via RIP homotypic interaction motif); this interaction induces RIPK1 phosphorylation and formation of a RIPK1-RIPK3 necroptosis-inducing complex (PubMed:11734559, PubMed:29883609, PubMed:19524512, PubMed:10358032, PubMed:29681455). Upon TNF-induced necrosis, the RIPK1-RIPK3 dimer further interacts with PGAM5 and MLKL; the formation of this complex leads to PGAM5 phosphorylation and increase in PGAM5 phosphatase activity (PubMed:22265414). Interacts (via the death domain) with TNFRSF6 (via the death domain) and TRADD (via the death domain) (PubMed:8612133). Is recruited by TRADD to TNFRSF1A in a TNF-dependent process (PubMed:24130170). Binds RNF216, EGFR, IKBKG, TRAF1, TRAF2 and TRAF3 (PubMed:8612133, PubMed:9927690, PubMed:11854271, PubMed:11116146). Interacts with BNLF1 (PubMed:10409763). Interacts with SQSTM1 upon TNF-alpha stimulation (PubMed:10356400). May interact with MAVS/IPS1 (PubMed:16127453). Interacts with ZFAND5 (PubMed:14754897). Interacts with RBCK1 (PubMed:17449468). Interacts with ZBP1 (By similarity). Interacts with BIRC2/c-IAP1, BIRC3/c-IAP2 and XIAP/BIRC4 (PubMed:21931591). Interacts (via kinase domain) with DAB2IP (via Ras-GAP domain); the interaction occurs in a TNF-alpha-dependent manner (PubMed:17389591). Interacts with ARHGEF2 (PubMed:21887730). Interacts (via protein kinase domain) with RFFL; involved in RIPK1 ubiquitination (PubMed:18450452). Interacts with RNF34; involved in RIPK1 ubiquitination (Ref.33). Interacts with TICAM1 and this interaction is enhanced in the presence of WDFY1 (PubMed:25736436). Interacts with PELI1 (PubMed:29883609). Interacts (via death domain) with CRADD (via death domain); the interaction is direct (PubMed:9044836). Component of complex IIa composed of at least RIPK1, FADD and CASP8 (By similarity). Interacts with MAP3K7, CFLAR, CASP8, FADD and NEMO (By similarity).SUBUNIT (Microbial infection) Interacts with mumps virus protein SH; this interaction inhibits downstream NF-kappa-B pathway activation.SUBUNIT (Microbial infection) Interacts with Murid herpesvirus 1 protein RIR1.SUBUNIT (Microbial infection) Interacts (via RIP homotypic interaction motif) with herpes simplex virus 1/HHV-1 protein RIR1/ICP6 (via RIP homotypic interaction motif); this interaction prevents necroptosis activation.SUBUNIT (Microbial infection) Interacts (via RIP homotypic interaction motif) with herpes simplex virus 2/HHV-2 protein RIR1/ICP10 (via RIP homotypic interaction motif); this interaction prevents necroptosis activation.DOMAIN The RIP homotypic interaction motif (RHIM) mediates interaction with the RHIM motif of RIPK1. Both motifs form a hetero-amyloid serpentine fold, stabilized by hydrophobic packing and featuring an unusual Cys-Ser ladder of alternating Ser (from RIPK1) and Cys (from RIPK3).DOMAIN The death domain mediates dimerization and activation of its kinase activity during necroptosis and apoptosis (PubMed:29440439). It engages other DD-containing proteins as well as a central (intermediate) region important for NF-kB activation and RHIM-dependent signaling (PubMed:10356400).PTM Proteolytically cleaved by CASP8 at Asp-324 (PubMed:10521396, PubMed:31827281, PubMed:31827280). Cleavage is crucial for limiting TNF-induced apoptosis, necroptosis and inflammatory response (PubMed:31827281, PubMed:31827280). Cleavage abolishes NF-kappa-B activation and enhances the interaction of TRADD with FADD (PubMed:10521396).PTM RIPK1 and RIPK3 undergo reciprocal auto- and trans-phosphorylation (PubMed:18408713, PubMed:19524513, PubMed:31827280). Phosphorylation of Ser-161 by RIPK3 is necessary for the formation of the necroptosis-inducing complex (PubMed:18408713). Phosphorylation at Ser-25 represses its kinase activity and consequently prevents TNF-mediated RIPK1-dependent cell death (PubMed:30988283). Phosphorylated at Ser-320 by MAP3K7 which requires prior ubiquitination with 'Lys-63'-linked chains by BIRC2/c-IAP1 and BIRC3/c-IAP2 (By similarity). This phosphorylation positively regulates RIPK1 interaction with RIPK3 to promote necroptosis but negatively regulates RIPK1 kinase activity and its interaction with FADD to mediate apoptosis (By similarity).PTM Ubiquitinated with 'Lys-11'-, 'Lys-48'-, 'Lys-63'- and linear-linked type ubiquitin (PubMed:15258597, PubMed:16603398, PubMed:18450452, PubMed:21455173, PubMed:21931591, PubMed:29883609, Ref.33). Polyubiquitination with 'Lys-63'-linked chains by TRAF2 induces association with the IKK complex (PubMed:15258597). Deubiquitination of 'Lys-63'-linked chains and polyubiquitination with 'Lys-48'-linked chains by TNFAIP3 leads to RIPK1 proteasomal degradation and consequently down-regulates TNF-alpha-induced NF-kappa-B signaling (PubMed:15258597). 'Lys-48'-linked polyubiquitination by RFFL or RNF34 also promotes proteasomal degradation and negatively regulates TNF-alpha-induced NF-kappa-B signaling (PubMed:18450452, Ref.33). Linear polyubiquitinated; the head-to-tail linear polyubiquitination ('Met-1'-linked) is mediated by the LUBAC complex and decreases protein kinase activity (PubMed:21455173). Deubiquitination of linear polyubiquitin by CYLD promotes the kinase activity (By similarity). Polyubiquitinated with 'Lys-48' and 'Lys-63'-linked chains by BIRC2/c-IAP1 and BIRC3/c-IAP2, leading to activation of NF-kappa-B (PubMed:21931591). Ubiquitinated with 'Lys-63'-linked chains by PELI1 (PubMed:29883609). Ubiquitination at Lys-377 with 'Lys-63'-linked chains by BIRC2/c-IAP1 and BIRC3/c-IAP2 is essential for its phosphorylation at Ser-320 mediated by MAP3K7 (By similarity). This ubiquitination is required for NF-kB activation, suppresses RIPK1 kinase activity and plays a critical role in preventing cell death during embryonic development (By similarity).SIMILARITY Belongs to the protein kinase superfamily. TKL Ser/Thr protein kinase family. 智人 NCBI分类法 9606 UniProt Q13546 377 平等的 泛腺苷酸赖氨酸 国防部 mod：01148 1 平等的 671 平等的 反应数据库ID版本77 5212672 数据库标识符。使用此URL在反弹中连接到此实例的网页：http：//www.reacectome.org/cgi-bin/eventbrowser?db=gk_current&id=5212672 反应 r - hsa - 5212672 1 Reactome稳定的标识符。使用此URL连接到Reactome中的此实例的网页://www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5212672.1 反应 //www.joaskin.com 1 从Reactome中的EntitySet转换而来 BIRC2、3、4 Reactome DB_ID: 5357900 Birc2. C-IAP1 杆状病毒IAP重复含蛋白3（细胞凋亡蛋白2的抑制剂）（HIAP2）（HIAP2）（C-IAP1）（TNFR2-TRAF信号复合蛋白2）（IAP同源物B） 杆状病毒IAP蛋白含有重复-2- 凋亡抑制蛋白2 HIAP2 HIAP-2 TNFR2-TRAF信号复合物蛋白2 IAP同族体B 反应DB_ID：50847 UniProt: Q13490 BIRC2 Birc2. API1 MIHB. RNF48 其调节不仅胱天蛋白酶和细胞凋亡，但还调制炎症信号和免疫力，促有丝分裂激酶信号传导和细胞增殖，以及细胞侵入和转移FUNCTION多功能蛋白。作为E3泛素蛋白连接酶调节NF-kappa-B信号通路，并通过相反的方向调控规范和非规范NF-kappa-B信号通路:作为规范通路的正调控因子，抑制非规范NF-kappa-B信号通路的结构性激活。用于靶蛋白的E3泛素 - 蛋白连接酶活性包括：RIPK1，RIPK2，RIPK3，RIPK4，CASP3，CASP7，CASP8，TRAF2，DIABLO / SMAC，MAP3K14 / NIK，MAP3K5 / ASK1，IKBKG / NEMO，IKBKE和MXD1 / MAD1。也可以用作所述NEDD8缀合途径的E3泛素 - 蛋白质连接酶，靶向neddylation和失活效应胱天蛋白酶。通过调节toll样受体(Toll-like receptor, TLRs)、结点样受体(Nodlike receptor, nrs)和RIG-I样受体(RIG-I like receptor, RLRs)，作为天然免疫信号的重要调节因子，统称为模式识别受体(pattern recognition receptor, PRRs)。保护细胞免受ripoptosome的自发形成，ripoptosome是一种大型多蛋白复合物，能够以caspase依赖和caspase独立的方式杀死癌细胞。通过泛素化RIPK1和CASP8来抑制ripoptosome的形成。能激发E2F1的转录活性。起着细胞cycle.ACTIVITY规的调制通过防止RING结构域二聚化和E2泛供体结合和激活作用的CARD结构域抑制E3泛素连接酶活性的激活。E3泛素 - 蛋白连接酶活性禁止显示细胞增殖和迁移的CARD结构域介导的自身抑制。 USP19 regulates the stability of BIRC2/c-IAP1 by preventing its ubiquitination.SUBUNIT Interacts with DIABLO/SMAC and with PRSS25; these interactions inhibit apoptotic suppressor activity. Interacts with CASP9. Interacts (via BIR domains) with TRAF2; the interaction is required for IKBKE ubiquitination. Interacts with E2F1, RIPK1, RIPK2, RIPK3, RIPK4, BIRC5/survivin and USP19. HSP90AB1 (PubMed:25486457). Interacts with UBXN1 (PubMed:25681446). Interacts with GSK3B (PubMed:18846110). Interacts with several death receptors, inclusing FAS, TNFRSF10A and TNFRSF10B (PubMed:18846110). Recruited to TNFRSF10B in the absence of receptor stimulation. When TNFRSF10B is stimulated, further recruited to the receptor and cleaved by caspases. Proteolytic fragments remain associated with TNFRSF10B (PubMed:18846110).TISSUE SPECIFICITY Present in many fetal and adult tissues. Mainly expressed in adult skeletal muscle, thymus, testis, ovary, and pancreas, low or absent in brain and peripheral blood leukocytes.DOMAIN The BIR domains mediate nuclear localization.DOMAIN The CARD domain is necessary to stabilize the protein and inhibit the activation of E3 ubiquitin-protein ligase activity of BIRC2/c-IAP1 by preventing RING domain dimerization and E2 ubiquitin donor binding and activation.PTM Auto-ubiquitinated and degraded by the proteasome in apoptotic cells.PTM Upon stimulation of death receptors, including TNFRSF10B, recruited to receptors and cleaved by caspases. Proteolytic fragments remain associated with the receptors. This cleavage presumably inactivates the protein.SIMILARITY Belongs to the IAP family. UniProt Q13490 1 平等的 618 平等的 反应数据库ID版本77 50847 数据库标识符。使用此URL连接到Reactome中的此实例的网页://www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=50847 反应 r - hsa - 50847 1 Reactome稳定的标识符。使用此URL连接到Reactome中的此实例的网页://www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-50847.1 API2 Birc3. C-IAP2 杆状病毒IAP含重复的蛋白2（凋亡蛋白1的抑制剂）（HIAP1）（HIAP-1）（C-IAP2）（TNFR2-TRAF信号传染性蛋白质1）（IAP同源物C） 杆状病毒IAP蛋白含有重复-3- 凋亡抑制蛋白1 HIAP1 HIAP-1 TNFR2-TRAF信号复合物蛋白1 IAP同族体C 细胞凋亡抑制剂2 反应DB_ID：50845 UniProt: Q13489 BIRC3 Birc3. API2 MIHC. RNF49 多功能蛋白，不仅调节半胱天冬酶和细胞凋亡，还调节炎症信号和免疫、有丝分裂激酶信号和细胞增殖、细胞侵袭和转移。作为E3泛素蛋白连接酶调节NF-kappa-B信号通路，并通过相反的方向调控规范和非规范NF-kappa-B信号通路:作为规范通路的正调控因子，抑制非规范NF-kappa-B信号通路的结构性激活。其E3泛素蛋白连接酶活性的靶蛋白包括:RIPK1、RIPK2、RIPK3、RIPK4、CASP3、CASP7、CASP8、IKBKE、TRAF1和BCL10。通过调节toll样受体(Toll-like receptor, TLRs)、结点样受体(Nodlike receptor, nrs)和RIG-I样受体(RIG-I like receptor, RLRs)，作为天然免疫信号的重要调节因子，统称为模式识别受体(pattern recognition receptor, PRRs)。保护细胞免受ripoptosome的自发形成，ripoptosome是一种大型多蛋白复合物，能够以caspase依赖和caspase独立的方式杀死癌细胞。通过ubiquitinated ripk1和Casp8抑制Ripoptosome形成。USP19通过阻止BIRC3/c-IAP2的泛素化来调节BIRC3/c-IAP2的稳定性。亚基与DIABLO/SMAC和PRSS25相互作用;这些相互作用抑制了凋亡抑制因子的活性。BIR基序区域与TNF受体相关因子1和2 (TRAF1和TRAF2)相互作用，形成一个异构体复合物，然后招募到肿瘤坏死因子受体2 (TNFR2)。IKBKE的泛素化、NFKBIA的降解和NF-kappa-B的活化需要与TRAF2的相互作用。 Interacts with RIP1, RIP2, RIP3, RIP4 and USP19.TISSUE SPECIFICITY Highly expressed in fetal lung, and kidney. In the adult, expression is mainly seen in lymphoid tissues, including spleen, thymus and peripheral blood lymphocytes.PTM Auto-ubiquitinated and degraded by the proteasome in apoptotic cells.DISEASE A chromosomal aberration involving BIRC3 is recurrent in low-grade mucosa-associated lymphoid tissue (MALT lymphoma). Translocation t(11;18)(q21;q21) with MALT1. This translocation is found in approximately 50% of cytogenetically abnormal low-grade MALT lymphoma.SIMILARITY Belongs to the IAP family. UniProt Q13489 1 平等的 604. 平等的 反应数据库ID版本77 50845 数据库标识符。使用此URL连接到Reactome中的此实例的网页://www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=50845 反应 r - hsa - 50845 1 Reactome稳定的标识符。使用此URL在反弹中连接到此实例的网页：http：//www.reacontome.org/cgi-bin/eventbrowser_st_id?st_id=r-hsa -50845.1 XIAP. 杆状病毒IAP蛋白含有重复-4- 凋亡抑制蛋白3 x -连锁凋亡抑制蛋白 连锁凋亡抑制蛋白 IAP样蛋白 HILP BIRC4. 反应DB_ID：50849 UniProt的：P98170 XIAP XIAP. API3 BIRC4. IAP3 多功能蛋白，不仅调节caspases和凋亡，还调节炎症信号和免疫，铜稳态，有丝分裂激酶信号，细胞增殖，细胞侵袭和转移。作为caspase的直接抑制剂。直接与CASP3和CASP7活性位点口袋结合，阻碍底物进入。通过将CASP9保持在单体的非活性状态，使其失活。作为E3泛素蛋白连接酶调控NF-kappa-B信号通路，其E3泛素蛋白连接酶活性的靶蛋白有:RIPK1、CASP3、CASP7、CASP8、CASP9、MAP3K2/MEKK2、DIABLO/SMAC、AIFM1、CCS和BIRC5/survivin。CCS的泛素化导致其伴侣对其生理靶点SOD1的活性增强，而不是蛋白酶体降解。MAP3K2/MEKK2和AIFM1的泛素化不会导致蛋白酶体降解。通过泛素化COMMD1并促进其蛋白酶体降解，在铜稳态中发挥作用。也可作为NEDD8连接途径的E3泛素蛋白连接酶，靶向效应caspases进行泛素化和失活。调节BMP信号通路和SMAD和MAP3K7/TAK1依赖通路，导致NF-kappa-B和JNK激活。 Acts as an important regulator of innate immune signaling via regulation of Nodlike receptors (NLRs). Protects cells from spontaneous formation of the ripoptosome, a large multi-protein complex that has the capability to kill cancer cells in a caspase-dependent and caspase-independent manner. Suppresses ripoptosome formation by ubiquitinating RIPK1 and CASP8. Acts as a positive regulator of Wnt signaling and ubiquitinates TLE1, TLE2, TLE3, TLE4 and AES. Ubiquitination of TLE3 results in inhibition of its interaction with TCF7L2/TCF4 thereby allowing efficient recruitment and binding of the transcriptional coactivator beta-catenin to TCF7L2/TCF4 that is required to initiate a Wnt-specific transcriptional program.SUBUNIT Monomer, and homodimer. Interacts with DIABLO/SMAC and with PRSS25; these interactions inhibit apoptotic suppressor activity. Interacts with TAB1/MAP3K7IP1 and AIFM1. Interaction with SMAC hinders binding of TAB1/MAP3K7IP1 and AIFM1. Interacts with TCF25 and COMMD1. Interacts with SEPTIN4 isoform 6, but not with other SEPTIN4 isoforms. Interacts with RIP1, RIP2, RIP3, RIP4, CCS and USP19. Interacts (via BIR 2 domain and BIR 3 domain) with HAX1 (via C-terminus) and this interaction blocks ubiquitination of XIAP/BIRC4. Interacts with the monomeric form of BIRC5/survivin. Interacts with TLE3 and TCF7L2/TCF4. Interacts (via BIR 3 and RING domains) with PDCL3 (PubMed:19012568).TISSUE SPECIFICITY Ubiquitous, except peripheral blood leukocytes.DOMAIN The first BIR domain is involved in interaction with TAB1/MAP3K7IP1 and is important for dimerization. The second BIR domain is sufficient to inhibit CASP3 and CASP7, while the third BIR is involved in CASP9 inhibition. The interactions with DIABLO/SMAC and PRSS25 are mediated by the second and third BIR domains.PTM S-Nitrosylation down-regulates its E3 ubiquitin-protein ligase activity.PTM Autoubiquitinated.SIMILARITY Belongs to the IAP family.CAUTION Was originally shown to be phosphorylated at Ser-87 by PKB, protecting the protein from ubiquitination and proteasomal degradation (PubMed:14645242). However, this work was later retracted (PubMed:27825084). UniProt P98170 1 平等的 497 平等的 反应数据库ID版本77 50849 数据库标识符。使用此URL连接到Reactome中的此实例的网页://www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=50849 反应 r - hsa - 50849 2 Reactome稳定的标识符。使用此URL连接到Reactome中的此实例的网页://www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-50849.2 反应数据库ID版本77 5357900 数据库标识符。使用此URL连接到该实例的网页中Reactome：//www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=5357900 反应 r - hsa - 5357900 1 Reactome稳定的标识符。使用此URL连接到该实例的网页中Reactome：//www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5357900.1 1 Traf2. TNF受体相关因子2 肿瘤坏死因子2受体相关蛋白 Reactome DB_ID: 66370 UniProt: Q12933 TRAF2 Traf2. TRAP3 功能对NF-κ-B和JNK的活性，并在细胞存活和凋亡的调控中发挥核心作用。所需的正常抗体同种型转换选自IgM与IgG。具有E3泛素 - 蛋白连接酶的活性，并促进“靶蛋白，如BIRC3，RIPK1和TICAM1的赖氨酸63'联泛素化。是几个E3泛素 - 蛋白连接酶复合物的必需的构成，在那里它通过使它们相互接触与其他E3泛素连接酶促进靶蛋白的泛素化。调控对BIRC2和BIRC3蛋白水平通过抑制它们的自身泛素化和随后的降解;这不依赖于TRAF2 RING型锌指结构域。起着由EIF2AK2 / PKR介导NF-κ-B的活化的作用。在复合体与BIRC2或BIRC3，促进IKBKE.ACTIVITY规的泛素化具有非常低的E3泛素在不存在鞘氨醇-1-磷酸的连接酶活性。E3泛素连接酶活强烈地受细胞质鞘氨醇-1- phosphate.PATHWAY蛋白质修饰活性;蛋白质同源三聚体ubiquitination.SUBUNIT（搜索PubMed：8069916）。 Heterotrimer with TRAF1 (PubMed:8069916). Heterotrimer with TRAF3 (via TRAF domain) (PubMed:15383523, PubMed:20447407). The domain containing the RING-type and the first TRAF-type zinc finger can also form homodimers (in vitro) (PubMed:19810754). Interacts with TNFRSF1B/TNFR2 (PubMed:7639698, PubMed:8069916, PubMed:10206649). Interacts with TNFRSF5/CD40 (PubMed:9718306). Interacts with TNFRSF4, TNFRSF7/CD27, TNFRSF8/CD30, TNFRSF9/CD137, TNFRSF11A/RANK, TNFRSF13B/TACI, TNFRSF14, TNFRSF16/NGFR, TNFRSF17/BCMA, TNFRSF18/AITR, TNFRSF19/TROY, TNFRSF19L/RELT and EDAR (PubMed:8627180, PubMed:9153189, PubMed:9692890, PubMed:9488716, PubMed:9774460, PubMed:9607925, PubMed:9418902, PubMed:10037686, PubMed:10514511, PubMed:10809768, PubMed:10880535, PubMed:11035039, PubMed:10411888). Stimulation of TNF-alpha receptor TNFRSF1A leads to the formation of two distinct signaling complexes. Plasma membrane-bound complex I is composed of TNFRSF1A, TRADD, RIPK1, TRAF2 and BIRC2/c-IAP1 or BIRC3 which interacts with CHUCK/IKK-alpha, IKBKB/IKK-beta and IKBKG/IKK-gamma promoting cell survival (PubMed:21307340, PubMed:18981220). Subsequently, TRADD, RIPK1 and TRAF2 dissociate from TNFRSF1A and form cytoplasmic complex II with FADD and caspase CASP8 promoting cell apoptosis (PubMed:21307340). Interacts with TRADD (PubMed:10892748). Identified in a complex with TNFRSF1A, RIPK1 and IKBKB/IKK-beta (PubMed:18981220). Interacts with RIPK2 (PubMed:9705938). Interacts with BIRC2 and BIRC3 N-terminus; a single BIRC2 or BIRC3 molecule interacts with a heterotrimer formed by TRAF1 and TRAF2, or a TRAF2 homotrimer (PubMed:11907583, PubMed:19506082, PubMed:20447407, PubMed:20385093). Identified in a complex composed of TRAF2, TRAF3, BIRC2 and BIRC3 (By similarity). Interacts with BIRC2; the interaction promotes BIRC2 stability (PubMed:19506082). Interaction with BIRC2 and/or BIRC3 is essential for ubiquitination of IKBKE, degradation of NFKBIA and activation of NF-kappa-B (By similarity). Within complex I, phosphorylated TRAF2 interacts (via 'Lys-63'-linked polyubiquitin chains) with CHUCK/IKK-alpha, IKBKB/IKK-beta, IKBKG/IKK-gamma TAB2, TAB3 and TAK1 in response to TNF-alpha stimulation (PubMed:19150425). Within complex I, interacts with UXT isoform 1 (via TPQE motif); the interaction prevents the recruitment of FADD and CASP8/caspase 8 to complex I (PubMed:21307340). Forms a complex composed of TNFRSF8/CD30 or TNFRSF1B/TNFR2, and TRAF1, TRAF2 and E3 ligase TRAIP (PubMed:9104814). Within the complex, interacts with TRAIP; the interaction inhibits TRAF2-mediated NF-kappa B activation (PubMed:9104814). Component of a complex composed of TANK and TBK1 (PubMed:10581243). Interacts with TRPC4AP (By similarity). Interacts with MAP3K1/MEKK1, MAP3K5/ASK1 and MAP3K11/MLK3 in response to TNF-alpha stimulation; the interaction leads to JNK activation (PubMed:10346818, PubMed:19918265, PubMed:9774977). Component of a complex composed of MAP3K14/NIK BIRC3 and TRAF3; the interaction leads to BIRC2/3-mediated ubiquitination of TRAF3 upon CD40 engagement in a TRAF2-dependent manner (By similarity). Interacts with MAP3K14/NIK in response to TNF-alpha stimulation; the interaction leads to NF-kappa B activation (PubMed:9020361). Interacts with PEG3; the interaction may promote TRAF2-mediated NF-kappa B activation (By similarity). Interacts with HIVEP3; the interaction may inhibit TNF-alpha-TRAF2-mediated NF-kappa B and JNK activation (By similarity). Interacts with TANK/ITRAF; the interaction prevents interaction between TNFRSF1B/TNFR2 and TRAF2 (PubMed:8710854). Interacts with deubiquitinating enzyme CYLD; the interaction results in the deubiquitination and inactivation of TRAF2 (PubMed:12917691). Interacts with SIAH2; the interaction leads to TRAF2 ubiquitination and degradation (PubMed:12411493). Interacts with E2 conjugating enzyme UBE2N/Ubc13, E3 ligase ITCH and RNF11 in response to TNF-alpha stimulation (By similarity). Interacts with ubiquitin-editing enzyme TNFAIP3/A20 in response to TNF-alpha stimulation; the interaction promotes TRAF2 dissociation from UBE2N/Ubc13, ITCH, RNF11 and TAX1BP1 and prevents prolonged TRAF-2 ubiquitination (By similarity). Interacts with TAX1BP1 in response to TNF-alpha stimulation; the interaction promotes TRAF2 dissociation from UBE2N/Ubc13 and TNFAIP3/A20, and prevents prolonged TRAF-2 ubiquitination (By similarity). Interacts (via C-terminus) with EIF2AK2/PKR (via the kinase catalytic domain) (PubMed:15121867). Interacts with deubiquitinating enzyme USP48 (PubMed:16214042). Interacts with PTPN2; probably involved in TNF-mediated signaling (PubMed:15696169). Interacts with Toll-like receptor TLR4/3 adapter TICAM1/TRIF; the interaction may promote TICAM1 ubiquitination (PubMed:20047764). Interacts with kinase/endoribonuclease ERN1/IRE1 and DAB2IP in response to ER stress; the interaction requires DAB2IP (By similarity). Interacts with ERN1/IRE1 and TAOK3 in response to ER stress; the interaction may promote TRAF2 phosphorylation (PubMed:11278723). Interacts (via zinc fingers) with DAB2IP (via C-terminus PER domain)in response to TNF-alpha stimulation (PubMed:15310755, PubMed:17389591). Interacts with CASP8AP2/FLASH (By similarity). Interacts with NFATC2IP; the interaction may repress IL-4 production in T cells (By similarity). Interacts with kinase CDK9 (PubMed:9827693). Interacts with sphingosine kinase 1 SPHK1 (PubMed:20577214). Interacts with kinase TNIK (PubMed:10521462). Interacts with TRAFD1 (By similarity). Interacts with DNA phosphodiesterase TDP2 (PubMed:10764746). Interacts with MAVS/IPS1 (PubMed:16153868). Interacts with CARD14 (PubMed:21302310). Interacts with Epstein-Barr virus LMP1/BNFL1 (PubMed:10411888). Interacts with GPS2 (By similarity). Interacts with XPNPEP3 (PubMed:25609706). Interacts with RIPK3 (PubMed:29883609). Interacts with RELL2 (PubMed:19969290). Interacts with LRRC19 (PubMed:25026888).DOMAIN The coiled coil domain mediates homo- and hetero-oligomerization.DOMAIN The MATH/TRAF domain binds to receptor cytoplasmic domains.DOMAIN The RING-type zinc finger domain is essential for E3 ubiquitin-protein ligase activity. It is not essential for the stabilization of BIRC2, or for the ubiquitination of RIPK1 in response to TNFR1 signaling.PTM Phosphorylated at several serine residues within the first 128 amino acid residues. Phosphorylated at Thr-117 in response to signaling via TNF and TNFRSF1A. Phosphorylation at Thr-117 is required for 'Lys-63'-linked polyubiquitination, but not for 'Lys-48'-linked polyubiquitination. Phosphorylation at Thr-117 is important for interaction with IKKA and IKKB, activation of IKK and subsequent activation of NF-kappa-B.PTM Undergoes both 'Lys-48'-linked and 'Lys-63'-linked polyubiquitination. Polyubiquitinated via 'Lys-63'-linked ubiquitin in response to TNF signaling; this requires prior phosphorylation at Thr-117. 'Lys-63'-linked polyubiquitination promotes TRAF2-mediated activation of NF-kappa-B. Can be polyubiquitinated at several Lys residues via 'Lys-48'-linked ubiquitin chains in response to TNF signaling, leading to proteasomal degradation. Autoubiquitinated, leading to its subsequent proteasomal degradation. Polyubiquitinated by BIRC2 and SIAH2, leading to its subsequent proteasomal degradation. Deubiquitinated by CYLD, a protease that specifically cleaves 'Lys-63'-linked polyubiquitin chains. Ubiquination is inhibited by LRRC19; inhibits proteasomal degradation (PubMed:25026888).SIMILARITY Belongs to the TNF receptor-associated factor family. A subfamily.CAUTION Was reported to interact with IL15RA (PubMed:10463949). However, this work was later retracted (PubMed:21357251). UniProt Q12933 2 平等的 501 平等的 反应数据库ID版本77 66370. 数据库标识符。使用此URL将此实例的Web页面连接到Reactome：http：//www.reacontome.org/cgi-bin/eventbrowser?db=gk_current&id=66370 反应 r - hsa - 66370 1 反应稳定标识符。使用此URL连接到Reactome中此实例的网页：//www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-66370.1 3. TRADD TNFR1相关死亡域蛋白 肿瘤坏死因子受体1型相关死亡结构域蛋白 通过死亡域与tnfrsf1a相关 Reactome DB_ID: 66376 UniProt的：Q15628 TRADD TRADD 核形式作为肿瘤抑制因子，通过阻止TRIP12对CDKN2A亚型p19ARF/ARF的泛素化和降解:通过与TRIP12相互作用，导致破坏TRIP12与CDKN2A亚型p19ARF/ARF之间的相互作用(通过相似性)。TNFRSF1A/TNFR1的适配分子，特异性与激活的TNFRSF1A/TNFR1的细胞质结构域结合，介导其与FADD的相互作用。TRADD过表达导致两种主要的tnf诱导反应，凋亡和NF-kappa-B的激活。tnf - α受体TNFRSF1A的亚单位刺激导致两种不同的信号复合物的形成。质膜结合复合物I由TNFRSF1A、TRADD、RIPK1、TRAF2和BIRC2/c-IAP1或BIRC3组成，与CHUCK/IKK-alpha、IKBKB/IKK-beta和IKBKG/IKK-gamma相互作用，促进细胞存活(PubMed:7758105, PubMed:8612133, PubMed:14585990, PubMed:21307340)。随后，TRADD、RIPK1和TRAF2与TNFRSF1A分离，与FADD和caspase CASP8形成细胞质复合物II，促进细胞凋亡(PubMed:21307340)。在复合物I中，与TNFRSF1A/TNFR1、TRAF2和激酶RIPK1相互作用(PubMed:7758105, PubMed:10892748, PubMed:8612133)。在复合物I中，与TRPC4AP相互作用;相互作用促进NF-kappa B激活(PubMed:14585990)。UXT1与络合物I结合; the interaction prevents the formation of complex II (PubMed:21307340). Within complex I Interacts with scaffold protein DAB2IP (PubMed:15310755). Interacts with autophagy receptor SQSTM1 (PubMed:10356400). Interacts with E3 ligase TRIP12 (By similarity). Interacts with kinase HIPK2 (PubMed:11032752). Interacts with keratin KRT14 (PubMed:11684708). Interacts with keratin KRT18 (PubMed:11684708). Interacts with keratins KRT16 and KRT17 (By similarity). Interacts with FADD (By similarity). Interacts with TOMM70 (PubMed:20628368).TISSUE SPECIFICITY Found in all examined tissues.DOMAIN Requires the intact death domain to associate with TNFRSF1A/TNFR1. UniProt Q15628 1 平等的 312. 平等的 反应数据库ID版本77 66376 数据库标识符。使用此URL在反垃圾中连接到此实例的网页：http：//www.reacontome.org/cgi-bin/eventbrowser?db=gk_current&id=66376 反应 r - hsa - 66376 1 Reactome稳定的标识符。使用此URL连接到该实例的网页中Reactome：//www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-66376.1 3. 从Reactome中的EntitySet转换而来 tnf三聚物:TNF-R1三聚物 Reactome DB_ID: 3371401 tnf: TNFR1 Reactome DB_ID: 74277 p60 TNFRSF1A (22 - 455) TNF-RI 肿瘤坏死因子受体超家族构件1A前体（P60）（TNF-R1）（TNF-RI）（P55）（CD120A）（含有：肿瘤坏死因子结合蛋白1（TBPI）） 肿瘤坏死因子受体超家族成员1A的前体 TNF-R1 过去 CD120A 肿瘤坏死因子结合蛋白1 TBPI Reactome DB_ID：66344 UniProt的：P19438 TNFRSF1A tnfrsf1a. TNFAR TNFR1 FUNCTION受体TNFSF2 / TNF-α和同源三聚体TNFSF1 /淋巴毒素-α。适配器分子FADD募集的caspase-8的激活受体。将得到的死亡诱导信号复合物（DISC）进行胱天蛋白酶-8的蛋白水解激活这启动胱天蛋白酶（天冬氨酸特异性半胱氨酸蛋白酶）介导的细胞凋亡的后续级联。有助于非杀细胞TNF效应，包括抗病毒状态和酸sphingomyelinase.SUBUNIT结合TNF的细胞外结构域导致同三聚的激活的诱导。聚集的死亡结构域提供了一个新的分子界面相互作用特异性地与TRADD的死亡结构域。各种TRADD相互作用的蛋白质如TRAFS，RIPK1和可能FADD，通过它们与TRADD关联招募到复杂。此复合物激活至少两个不同的信号传导级联，细胞凋亡和NF-κ-乙信令。与BAG4，BABAM2，FEM1B，GRB2，SQSTM1和TRPC4AP相互作用（：10356400，PubMed的：10359574，PUBMED：10542291，PUBMED：15465831，PUBMED：8387891 PUBMED，PUBMED：9915703）。与NOL3（通过CARD结构域）直接相互作用;抑制TNF信号传导途径（通过相似性）。 Interacts with SH3RF2, TRADD and RIPK1. SH3RF2 facilitates the recruitment of RIPK1 and TRADD to TNFRSF1A in a TNF-alpha-dependent process (PubMed:24130170). Interacts with PGLYRP1; this interaction is important for cell death induction (PubMed:26183779).SUBUNIT (Microbial infection) Interacts with mumps virus protein SH; this interaction inhibits downstream NF-kappa-B pathway activation.SUBUNIT (Microbial infection) Interacts with HCV core protein.SUBUNIT (Microbial infection) Interacts with human cytomegalovirus/HHV-5 protein UL138.SUBUNIT (Microbial infection) Interacts with host TNFRSF1A; this interaction leads to the stimulation of both surface expression and shedding of TNFRSF1A.DOMAIN The domain that induces A-SMASE is probably identical to the death domain. The N-SMASE activation domain (NSD) is both necessary and sufficient for activation of N-SMASE.DOMAIN Both the cytoplasmic membrane-proximal region and the C-terminal region containing the death domain are involved in the interaction with TRPC4AP.PTM The soluble form is produced from the membrane form by proteolytic processing. UniProt P19438 22 平等的 455. 平等的 反应数据库ID版本77 66344 数据库标识符。使用此URL连接到Reactome中的此实例的网页://www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=66344 反应 r - hsa - 66344 1 反应稳定标识符。使用此URL连接到Reactome中此实例的网页：//www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-66344.1 3. tnf三聚物 肿瘤坏死因子(1 - 233)三聚物 Reactome DB_ID：3371351 TNF-a TNF（1-233） tnf 肿瘤坏死因子前体（TNF-α）（肿瘤坏死因子配体超家族成员2）（恶病质素） 肿瘤坏死因子前体 肿瘤坏死因子配体超家族成员2 Cachectin. Reactome DB_ID：66220 UniProt: P01375肿瘤坏死因子 肿瘤坏死因子 TNFA TNFSF2 与TNFRSF1A/TNFR1和TNFRSF1B/TNFBR结合的细胞因子。它主要由巨噬细胞分泌，可诱导某些肿瘤细胞系的细胞死亡。它是直接作用或刺激白细胞介素-1分泌引起发热的强效热原，与恶病质的诱导有关，在一定条件下可刺激细胞增殖，诱导细胞分化。通过FOXP3去磷酸化损伤类风湿关节炎患者的调节性t细胞(Treg)功能。上调蛋白磷酸酶1 (PP1)的表达，PP1将FOXP3关键的“ser418”残基去磷酸化，从而使FOXP3失活，导致Treg细胞功能缺陷(PubMed:23396208)。在RT4v6膀胱癌细胞系中，bcg刺激的中性粒细胞联合DIABLO/SMAC模拟物的抗癌作用中，细胞死亡的关键中介物(PubMed:22517918, PubMed:16829952, PubMed:23396208)。通过抑制胰岛素诱导的IRS1酪氨酸磷酸化和胰岛素诱导的葡萄糖摄取，诱导脂肪细胞的胰岛素抵抗。在脂肪细胞中诱导GKAP42蛋白降解，这是tnf诱导的胰岛素抵抗的部分原因(通过相似性)。通过与IL1B和IL6协同诱导VEGF的产生，在血管生成中发挥作用(PubMed:12794819)。TNF胞内结构域(ICD)的形成诱导树突状细胞中IL12的产生。亚基Homotrimer。与SPPL2B交互。PTM The soluble form derives from the membrane form by proteolytic processing. The membrane-bound form is further proteolytically processed by SPPL2A or SPPL2B through regulated intramembrane proteolysis producing TNF intracellular domains (ICD1 and ICD2) released in the cytosol and TNF C-domain 1 and C-domain 2 secreted into the extracellular space.PTM The membrane form, but not the soluble form, is phosphorylated on serine residues. Dephosphorylation of the membrane form occurs by binding to soluble TNFRSF1A/TNFR1.PTM O-glycosylated; glycans contain galactose, N-acetylgalactosamine and N-acetylneuraminic acid.POLYMORPHISM Genetic variations in TNF influence susceptibility to hepatitis B virus (HBV) infection [MIM:610424].POLYMORPHISM Genetic variations in TNF are involved in susceptibility to malaria [MIM:611162].SIMILARITY Belongs to the tumor necrosis factor family. UniProt P01375 1 平等的 233 平等的 反应数据库ID版本77 66220 数据库标识符。使用此URL连接到Reactome中此实例的网页：//www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=66220 反应 R-HSA-66220 1 Reactome稳定的标识符。使用此URL连接到该实例的网页中Reactome：//www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-66220.1 3. 反应数据库ID版本77 3371351 数据库标识符。使用此URL连接到Reactome中的此实例的网页://www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=3371351 反应 r - hsa - 3371351 2 Reactome稳定的标识符。使用此URL连接到Reactome中的此实例的网页://www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-3371351.2 1 反应数据库ID版本77 74277 数据库标识符。使用此URL连接到该实例的网页中Reactome：//www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=74277 反应 r - hsa - 74277 1 Reactome稳定的标识符。使用此URL连接到Reactome中的此实例的网页://www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-74277.1 可溶性TNF-α：TNFR1 Reactome DB_ID: 3371397 3. tnf三聚物 tnf -三聚体，可溶性形式 Reactome DB_ID：3371370 细胞外区域 基因本体论 去:0005576 肿瘤坏死因子 肿瘤坏死因子(77 - 233) tnf 肿瘤坏死因子 TNFA_HUMAN Cachectin. Reactome DB_ID: 976821 77 平等的 233 平等的 反应数据库ID版本77 976821 数据库标识符。使用此URL连接到Reactome中的此实例的网页://www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=976821 反应 r - hsa - 976821 3. Reactome稳定的标识符。使用此URL在反垃圾中连接到此实例的网页：http：//www.reacontome.org/cgi-bin/eventbrowser_st_id?st_id=r-hsa-976821.3 3. 反应数据库ID版本77 3371370 数据库标识符。使用此URL连接到Reactome中的此实例的网页://www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=3371370 反应 R-HSA-3371370 2 Reactome稳定的标识符。使用此URL将此实例的网页连接到反乐中：http：//www.reacectome.org/cgi-bin/eventbrowser_st_id?st_id=r-hsa-3371370.2 1 反应数据库ID版本77 3371397 数据库标识符。使用此URL将此实例的Web页面连接到Reactome：http：//www.reacontome.org/cgi-bin/eventbrowser?db=gk_current&id=3371397 反应 R-HSA-3371397 1 Reactome稳定的标识符。使用此URL连接到Reactome中的此实例的网页://www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-3371397.1 反应数据库ID版本77 3371401. 数据库标识符。使用此URL连接到该实例的网页中Reactome：//www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=3371401 反应 R-HSA-3371401 1 Reactome稳定的标识符。使用此URL连接到该实例的网页中Reactome：//www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-3371401.1 1 反应数据库ID版本77 5357756 数据库标识符。使用此URL将此实例的网页连接到Reactome：http：//www.reacontome.org/cgi-bin/eventbrowser?db=gk_current&id=5357756 反应 R-HSA-5357756 7 Reactome稳定的标识符。使用此URL将此实例的Web页面连接到Reactome：http：//www.reacontome.org/cgi-bin/eventbrowser_st_id?st_id=r-hsa -5357756.7 索尔德 可能是泛素羧基末端水解酶CYLD CYLD_HUMAN Reactome DB_ID: 741420 UniProt: Q9NQC7 CYLD 索尔德 CYLD1 KIAA0849 HSPC057 功能:去泛素酶，特异性裂解'Lys-63'-和线性'Met-1'-linked polybiquitin链，参与NF-kappa-B激活和tnf - α诱导的坏死(PubMed:18636086, PubMed:26670046, PubMed:27458237, PubMed:26997266, PubMed:27591049, PubMed:29291351, PubMed:18313383)。在导致NF-kappa-B激活的通路调控中发挥重要作用(PubMed:12917689, PubMed:12917691)。通过影响NF-kappa-B的激活来调节细胞的存活、增殖和分化(PubMed:12917690)。Wnt信号负调控因子(PubMed:20227366)。抑制HDAC6，从而促进α -微管蛋白的乙酰化和微管的稳定(PubMed:19893491)。在微管动力学调控中发挥作用，从而有助于调节细胞增殖、细胞极化、细胞迁移和血管生成(PubMed:18222923, PubMed:20194890)。正常的细胞周期进展和正常的细胞分裂所需(PubMed:17495026, PubMed:19893491)。抑制NF-kappa-B的核易位(PubMed:18636086)。通过其对NF-kappa-B激活的影响，在炎症和先天性免疫反应中发挥作用(PubMed:18636086)。对胸腺内自然杀伤细胞的成熟是必不可少的，但对未成熟的自然杀伤细胞的继续生存是必需的(通过相似性)。 Negatively regulates TNFRSF11A signaling and osteoclastogenesis (By similarity). Involved in the regulation of ciliogenesis, allowing ciliary basal bodies to migrate and dock to the plasma membrane; this process does not depend on NF-kappa-B activation (By similarity). Ability to remove linear ('Met-1'-linked) polyubiquitin chains regulates innate immunity and TNF-alpha-induced necroptosis: recruited to the LUBAC complex via interaction with SPATA2 and restricts linear polyubiquitin formation on target proteins (PubMed:26997266, PubMed:26670046, PubMed:27458237, PubMed:27591049). Regulates innate immunity by restricting linear polyubiquitin formation on RIPK2 in response to NOD2 stimulation (PubMed:26997266). Involved in TNF-alpha-induced necroptosis by removing linear ('Met-1'-linked) polyubiquitin chains from RIPK1, thereby regulating the kinase activity of RIPK1 (By similarity). Removes 'Lys-63' linked polyubiquitin chain of MAP3K7, which inhibits phosphorylation and blocks downstream activation of the JNK-p38 kinase cascades (PubMed:29291351).ACTIVITY REGULATION Inhibited by phosphorylation at serine residues.SUBUNIT Interacts (via CAP-Gly domain) with IKBKG/NEMO (via proline-rich C-terminal region) (PubMed:12917689, PubMed:12917690, PubMed:12917691, PubMed:15341735). Interacts with TRAF2 and TRIP (PubMed:12917691, PubMed:14676304). Interacts with PLK1, DVL1, DVL3, MAVS, TBK1, IKKE and DDX58 (PubMed:17495026, PubMed:18636086, PubMed:20227366). Interacts (via CAP-Gly domain) with microtubules (PubMed:19893491). Interacts with HDAC6 and BCL3 (PubMed:19893491). Interacts with MAP3K7 (By similarity). Identified in a complex with TRAF6 and SQSTM1 (By similarity). Interacts with CEP350 (PubMed:25134987). Interacts with RNF31; the interaction is indirect and is mediated via SPATA2 (PubMed:26997266). Interacts with SPATA2 (via the PUB domain); the interaction is direct and recruits CYLD to the LUBAC complex, thereby regulating TNF-alpha-induced necroptosis (PubMed:27307491, PubMed:27458237, PubMed:27545878, PubMed:27591049).TISSUE SPECIFICITY Detected in fetal brain, testis, and skeletal muscle, and at a lower level in adult brain, leukocytes, liver, heart, kidney, spleen, ovary and lung. Isoform 2 is found in all tissues except kidney.PTM Ubiquitinated. Polyubiquitinated in hepatocytes treated with palmitic acid. Ubiquitination is mediated by E3 ligase TRIM47 and leads to proteasomal degradation.PTM Phosphorylated on several serine residues by IKKA and/or IKKB in response to immune stimuli. Phosphorylation requires IKBKG. Phosphorylation abolishes TRAF2 deubiquitination, interferes with the activation of Jun kinases, and strongly reduces CD40-dependent gene activation by NF-kappa-B.SIMILARITY Belongs to the peptidase C19 family. UniProt Q9NQC7 1 平等的 956. 平等的 反应数据库ID版本77 741420 数据库标识符。使用此URL连接到该实例的网页中Reactome：//www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=741420 反应 r - hsa - 741420 1 Reactome稳定的标识符。使用此URL将此实例的Web页面连接到Reactome：http：//www.reacontome.org/cgi-bin/eventbrowser_st_id?st_id=r-hsa-741420.1 CLIP3 CLIPR59 CAP-Gly接头蛋白3结构域的 Reactome DB_ID: 5212669 UniProt: Q96DZ5 CLIP3 CLIP3 CLIPR59 功能类似于细胞质连接蛋白。参与TGN内体动力学。可能调节AKT激酶家族的细胞区隔化并促进其细胞膜定位，从而在脂肪细胞葡萄糖转运中发挥作用。亚单位同型二聚体。与AKT1和AKT2相互作用；当AKT1和AKT2被磷酸化和激活时，AKT2的亲和力更高（PubMed:19139280）。与ZDHHC13相互作用（通过ANK重复序列）（PubMed:26198635）。与ZDHHC17相互作用（通过ANK重复序列）（PubMed:26198635，PubMed:28882895）。结构域微管结合被ANK重复序列和高尔基体定位区（GoLD）抑制。ZDHHC17的PTM棕榈酰化调节与质膜的结合。N末端的一半对于正确的高尔基体靶向是不必要的，而黄金区域是必需的。 UniProt Q96DZ5 1 平等的 547 平等的 反应数据库ID版本77 5212669 数据库标识符。使用此URL在反弹中连接到此实例的网页：http：//www.reacontome.org/cgi-bin/eventbrowser?db=gk_current&id=5212669 反应 r - hsa - 5212669 1 Reactome稳定的标识符。使用此URL连接到Reactome中的此实例的网页://www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5212669.1 CYLD：剪辑3：TNF：TNFR1：TRADD：K63PUB-RIP1：TRAF2：BIRC2 / 3 Reactome DB_ID: 5357950 1 1 1 反应数据库ID版本77 5357950 数据库标识符。使用此URL连接到Reactome中此实例的网页：//www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=5357950 反应 r - hsa - 5357950 1 Reactome稳定的标识符。使用此URL连接到Reactome中的此实例的网页://www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5357950.1 反应数据库ID版本77 5357928 数据库标识符。使用此URL连接到Reactome中的此实例的网页://www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=5357928 反应 R-HSA-5357928 1 Reactome稳定的标识符。使用此URL连接到Reactome中的此实例的网页://www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5357928.1 22297296. Pubmed 2012年 CLIPR-59调节TNF - ?-通过控制RIP1的泛素化诱导凋亡 Fujikura D 伊藤，M 千叶，S 原田T 佩雷斯,F 里德，JÇ 您,T 宫崎骏,T 细胞死亡Dis 3:e264 22435550 Pubmed 2012年 通过deubiquitinases NF-κB的调控 Harhaj,爱德华·W Dixit，Vishva M Immunol。启246:107-24