ZAP70 (zeta-chain-associated protein kinase 70) is a Syk-family cytoplasmic protein tyrosine kinase expressed in T cells, NK cells and thymocytes (and at low levels in pre-B and some CLL B cells). It consists of tandem N-terminal SH2 domains, an interdomain B linker carrying regulatory tyrosines (Y292, Y315, Y319) and a C-terminal kinase domain. In resting T cells ZAP70 is cytosolic and autoinhibited. After TCR engagement, LCK phosphorylates both tyrosines of the ITAMs in CD3 zeta (CD247) and the CD3 epsilon/gamma/delta chains; the tandem SH2 domains of ZAP70 bind these doubly phosphorylated ITAMs cooperatively, docking ZAP70 at the engaged TCR at the plasma membrane/immunological synapse and relieving autoinhibition. LCK then phosphorylates the activation loop (Y493) and interdomain B (Y319, which also binds the LCK SH2 domain), fully activating the kinase. Active ZAP70 phosphorylates the adaptors LAT and LCP2 (SLP-76), creating docking sites for PLCG1, GRB2/GADS, VAV1 and ITK that drive calcium, Ras-MAPK and NFAT signaling; it also phosphorylates substrates such as VAV1 and DUSP3 (VHR). Substrate choice is governed by an electrostatic filter: ZAP70 favours tyrosines flanked by acidic residues and disfavours nearby lysine or arginine, which selects LAT and SLP-76 sites and, together with its inability to phosphorylate ITAMs itself, makes it strictly dependent on LCK to initiate TCR signaling. Its activity is terminated by phosphatases (PTPN22, UBASH3A/B) and CBL-mediated ubiquitination. ZAP70 is essential for TCR signaling and thymic selection: biallelic loss-of-function mutations cause a combined immunodeficiency with absent CD8 T cells and non-functional CD4 T cells, while hypomorphic/activating combinations can cause autoimmunity.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0001772 immunological synapse | IEA GO_REF:0000107 | ACCEPT | Summary: ZAP70 is recruited to engaged TCR/CD3 at the immunological synapse (IEA from mouse Zap70 ortholog). Reason: ZAP70 docks on phosphorylated CD3/zeta ITAMs at the plasma membrane of the T cell-APC contact and colocalizes with RHOH in the immunological synapse; the orthology transfer from mouse is sound. Supporting Evidence: file:human/ZAP70/ZAP70-uniprot.txt Colocalizes together with RHOH in the immunological synapse. PMID:9813084 After antigenic stimulation, ZAP-70 rapidly associates with T cell receptor (TCR) subunits. |
| GO:0001784 phosphotyrosine residue binding | IEA GO_REF:0000107 | ACCEPT | Summary: Tandem SH2 domains of ZAP70 bind doubly phosphorylated ITAM tyrosines of CD3 zeta and CD3 epsilon. Reason: Phosphotyrosine binding by the tandem SH2 domains is the recruitment mechanism of ZAP70 and is directly demonstrated by binding assays with phospho-ITAM peptides; binding requires phosphorylation of both ITAM tyrosines. Core function. Supporting Evidence: PMID:7528772 Direct binding studies demonstrated that the tandem ZAP-70 SH2 domains bind phosphorylated, but not nonphosphorylated, TCR zeta cyt. PMID:7528772 the ZAP-70 interaction with the TCR requires prior phosphorylation of both tyrosine residues within a TAM motif PMID:7509083 This phosphorylation leads to the recruitment of a second cytoplasmic PTK, ZAP-70, through both of the ZAP-70 Src homology 2 domains and its phosphorylation. |
| GO:0002250 adaptive immune response | TAS PMID:20135127 ZAP70: a master regulator of adaptive immunity. | KEEP AS NON CORE | Summary: ZAP70 acts in the adaptive immune response as the proximal TCR kinase. Reason: True at a high level (ZAP70 deficiency causes combined immunodeficiency), but adaptive immune response is a very broad parent process; the specific process in which ZAP70 does the work is the T cell receptor signaling pathway (GO:0050852). Supporting Evidence: PMID:20135127 These studies demonstrated that ZAP70 was indeed at the crossroad of several signalling pathways that control T lymphocyte development and function. |
| GO:0004672 protein kinase activity | IEA GO_REF:0000120 | ACCEPT | Summary: Generic protein kinase activity (IEA). Reason: Correct but general; ZAP70 is a protein tyrosine kinase. The more specific GO:0004715 is used as the core term; this broader IEA is acceptable. Supporting Evidence: PMID:15292186 We crystallized and determined the three-dimensional structure of the catalytic subunit of ZAP-70 as a complex with staurosporine to 2.3 A resolution, utilizing an active kinase domain containing residues 327-606 |
| GO:0004713 protein tyrosine kinase activity | IBA GO_REF:0000033 | ACCEPT | Summary: Protein tyrosine kinase activity inferred from the PANTHER tyrosine kinase family tree. Reason: ZAP70 is a Syk-family cytoplasmic protein tyrosine kinase; its catalytic activity (EC 2.7.10.2) is established biochemically and structurally, and it directly phosphorylates LAT and LCP2/SLP-76 during TCR signaling. Core function. The IBA node placement within the tyrosine kinase family is appropriate; ZAP70 itself is among the experimental donors. Supporting Evidence: PMID:11368773 Zap-70 efficiently phosphorylates LAT on tyrosine residues at positions 226, 191, 171, 132 and 127. PMID:15292186 We crystallized and determined the three-dimensional structure of the catalytic subunit of ZAP-70 as a complex with staurosporine to 2.3 A resolution, utilizing an active kinase domain containing residues 327-606 |
| GO:0004713 protein tyrosine kinase activity | IDA PMID:15292186 The three-dimensional structure of the ZAP-70 kinase domain ... | ACCEPT | Summary: Recombinant ZAP70 kinase domain (residues 327-606) is catalytically active and was crystallized with staurosporine. Reason: ZAP70 is a Syk-family cytoplasmic protein tyrosine kinase; its catalytic activity (EC 2.7.10.2) is established biochemically and structurally, and it directly phosphorylates LAT and LCP2/SLP-76 during TCR signaling. Core function. Supporting Evidence: PMID:15292186 We crystallized and determined the three-dimensional structure of the catalytic subunit of ZAP-70 as a complex with staurosporine to 2.3 A resolution, utilizing an active kinase domain containing residues 327-606 |
| GO:0004713 protein tyrosine kinase activity | IEA GO_REF:0000120 | ACCEPT | Summary: Protein tyrosine kinase activity (IEA; InterPro/Rhea mapping). Reason: ZAP70 is a Syk-family cytoplasmic protein tyrosine kinase; its catalytic activity (EC 2.7.10.2) is established biochemically and structurally, and it directly phosphorylates LAT and LCP2/SLP-76 during TCR signaling. Core function. Supporting Evidence: PMID:11368773 Zap-70 efficiently phosphorylates LAT on tyrosine residues at positions 226, 191, 171, 132 and 127. |
| GO:0004713 protein tyrosine kinase activity | NAS PMID:1423621 ZAP-70: a 70 kd protein-tyrosine kinase that associates with... | ACCEPT | Summary: Original cloning of ZAP-70 as a novel PTK associating with TCR zeta. Reason: ZAP70 is a Syk-family cytoplasmic protein tyrosine kinase; its catalytic activity (EC 2.7.10.2) is established biochemically and structurally, and it directly phosphorylates LAT and LCP2/SLP-76 during TCR signaling. Core function. Supporting Evidence: PMID:1423621 ZAP-70 represents a novel PTK and is expressed in T and natural killer cells. |
| GO:0004713 protein tyrosine kinase activity | NAS PMID:8613493 A mutation in zap-70 protein tyrosine kinase results in a se... | ACCEPT | Summary: ZAP70 mutation in selective T cell deficiency abolishes kinase activity. Reason: ZAP70 is a Syk-family cytoplasmic protein tyrosine kinase; its catalytic activity (EC 2.7.10.2) is established biochemically and structurally, and it directly phosphorylates LAT and LCP2/SLP-76 during TCR signaling. Core function. Supporting Evidence: PMID:8613493 selective T-cell deficiency patients carry a mutation of zap-70 protein tyrosine kinase, resulting in a loss of the activity of this kinase |
| GO:0004713 protein tyrosine kinase activity | TAS Reactome:R-HSA-202174 | ACCEPT | Summary: Reactome: activated ZAP-70 phosphorylates LAT and SLP-76. Reason: ZAP70 is a Syk-family cytoplasmic protein tyrosine kinase; its catalytic activity (EC 2.7.10.2) is established biochemically and structurally, and it directly phosphorylates LAT and LCP2/SLP-76 during TCR signaling. Core function. Supporting Evidence: Reactome:R-HSA-202174 Activated ZAP-70 phosphorylates T-cell-specific adaptors, such as LAT and SLP-76 |
| GO:0004713 protein tyrosine kinase activity | TAS Reactome:R-HSA-202216 | ACCEPT | Summary: Reactome: ZAP-70 phosphorylates SLP-76 (LCP2) N-terminal tyrosines. Reason: ZAP70 is a Syk-family cytoplasmic protein tyrosine kinase; its catalytic activity (EC 2.7.10.2) is established biochemically and structurally, and it directly phosphorylates LAT and LCP2/SLP-76 during TCR signaling. Core function. Supporting Evidence: Reactome:R-HSA-202216 These tyrosine residues are phosphorylated by tyrosine kinase ZAP-70 |
| GO:0004713 protein tyrosine kinase activity | TAS Reactome:R-HSA-2395801 | ACCEPT | Summary: Reactome reaction centred on SYK phosphorylating LAT (DAP12 signaling); ZAP-70 is also named as a LAT kinase. Reason: The molecular function assertion (protein tyrosine kinase activity) is correct for ZAP70 irrespective of the SYK-centred reaction context; ZAP70 and SYK both phosphorylate LAT. Supporting Evidence: Reactome:R-HSA-2395801 Src family kinases, SYK and ZAP-70 efficiently phosphorylate LAT on these tyrosine residues PMID:11368773 Zap-70 efficiently phosphorylates LAT on tyrosine residues at positions 226, 191, 171, 132 and 127. |
| GO:0004713 protein tyrosine kinase activity | TAS Reactome:R-HSA-2396594 | ACCEPT | Summary: Reactome reaction centred on SYK phosphorylating SLP-76 in DAP12 signaling, by analogy to ZAP-70. Reason: ZAP70 is a genuine SLP-76/LCP2 kinase in T cells, so the tyrosine kinase activity annotation is correct even though this reaction context is SYK-centred. Supporting Evidence: Reactome:R-HSA-2396594 Phosphorylation may be mediated by SYK, analogous to the role of ZAP-70 in phosphorylating T-cell SLP-76 Reactome:R-HSA-202216 These tyrosine residues are phosphorylated by tyrosine kinase ZAP-70 |
| GO:0004713 protein tyrosine kinase activity | TAS Reactome:R-HSA-2424484 | ACCEPT | Summary: Reactome reaction for SYK-dependent BTK phosphorylation in myeloid DAP12 signaling; ZAP70 presumably included via a SYK/ZAP70 candidate set. Reason: The asserted MF (protein tyrosine kinase activity) is correct for ZAP70; the specific BTK reaction is SYK-driven in myeloid cells and is not itself evidence about ZAP70 substrates, but it does not change the correctness of the activity term. Supporting Evidence: Reactome:R-HSA-2424484 In myeloid cells BTK is phosphorylated on Y551 upon DAP12 activation in a SYK kinase-dependent manner. PMID:15292186 We crystallized and determined the three-dimensional structure of the catalytic subunit of ZAP-70 as a complex with staurosporine to 2.3 A resolution, utilizing an active kinase domain containing residues 327-606 |
| GO:0004713 protein tyrosine kinase activity | TAS Reactome:R-HSA-2424486 | ACCEPT | Summary: Reactome reaction for VAV2/VAV3 phosphorylation by SYK; ZAP70 presumably included via a SYK/ZAP70 candidate set. Reason: MF term is correct for ZAP70 (a Syk-family PTK that also phosphorylates VAV1); the reaction context is SYK-centred. Supporting Evidence: Reactome:R-HSA-2424486 This is mediated by SYK and Src-family tyrosine kinases PMID:23620790 Complex 5 contains ZAP70, CBAP, integrin Ξ²1 and Vav1, which upon phosphorylation of Vav1 by ZAP70 quickly dissociates from integrin Ξ²1 and transforms into complex 6 (ZAP70/CBAP/pVav1) that can further activate downstream targets like Rac1. |
| GO:0004715 non-membrane spanning protein tyrosine kinase activity | IDA PMID:12447358 Tyrosine phosphorylation of VHR phosphatase by ZAP-70. | ACCEPT | Summary: ZAP70 phosphorylates the dual-specificity phosphatase VHR (DUSP3) at Y138. Reason: Direct in vitro/in-cell phosphorylation of a protein substrate by ZAP70; non-membrane spanning PTK activity is the most accurate MF term for ZAP70 (cytoplasmic Syk-family kinase). Core. Supporting Evidence: PMID:12447358 is phosphorylated at Y138 by ZAP-70 |
| GO:0004715 non-membrane spanning protein tyrosine kinase activity | IDA PMID:9489702 LAT: the ZAP-70 tyrosine kinase substrate that links T cell ... | ACCEPT | Summary: ZAP-70/Syk phosphorylate LAT, recruiting downstream signaling proteins. Reason: Identification of LAT as the key ZAP70 substrate linking TCR to downstream signaling. Core. Supporting Evidence: PMID:9489702 We show that this protein is phosphorylated by ZAP-70/Syk protein tyrosine kinases leading to recruitment of multiple signaling molecules. |
| GO:0004715 non-membrane spanning protein tyrosine kinase activity | IEA GO_REF:0000120 | ACCEPT | Summary: Non-membrane spanning PTK activity (IEA; ARBA/InterPro/EC). Reason: ZAP70 is a Syk-family cytoplasmic protein tyrosine kinase; its catalytic activity (EC 2.7.10.2) is established biochemically and structurally, and it directly phosphorylates LAT and LCP2/SLP-76 during TCR signaling. Core function. Supporting Evidence: PMID:11368773 Zap-70 efficiently phosphorylates LAT on tyrosine residues at positions 226, 191, 171, 132 and 127. |
| GO:0004715 non-membrane spanning protein tyrosine kinase activity | TAS PMID:20135127 ZAP70: a master regulator of adaptive immunity. | ACCEPT | Summary: Review describing ZAP70 as the TCR-proximal tyrosine kinase. Reason: ZAP70 is a Syk-family cytoplasmic protein tyrosine kinase; its catalytic activity (EC 2.7.10.2) is established biochemically and structurally, and it directly phosphorylates LAT and LCP2/SLP-76 during TCR signaling. Core function. Supporting Evidence: PMID:20135127 These studies demonstrated that ZAP70 was indeed at the crossroad of several signalling pathways that control T lymphocyte development and function. |
| GO:0005515 protein binding | IPI PMID:10318843 Tyrosine 319 in the interdomain B of ZAP-70 is a binding sit... | MODIFY | Summary: Lck SH2 domain binds phospho-Tyr319 in ZAP70 interdomain B, promoting ZAP70 activation. Reason: Replace generic protein binding with protein kinase binding: ZAP70 binds the Src-family kinase LCK (via pY319 engaging the LCK SH2 domain), which positions LCK to phosphorylate and activate ZAP70. Non-core regulatory interaction. Proposed replacements: protein kinase binding Supporting Evidence: PMID:10318843 Tyr319-mediated binding of the SH2 domain of Lck is crucial for ZAP-70 activation PMID:10318843 One essential function of Lck in this process is to phosphorylate ZAP-70 and up-regulate its catalytic activity. |
| GO:0005515 protein binding | IPI PMID:10704231 Activation of Zap-70 tyrosine kinase due to a structural rea... | MODIFY | Summary: ZAP70 binding to diphosphorylated zeta ITAM via its SH2 domains activates the kinase. Reason: The interaction is the SH2-domain-mediated binding of ZAP70 to doubly phosphorylated ITAM tyrosines of the TCR zeta chain (CD247) / CD3 chains; this is captured informatively by phosphotyrosine residue binding (GO:0001784). Proposed replacements: phosphotyrosine residue binding Supporting Evidence: PMID:10704231 Binding of ZAP-70 to the phosphorylated immunoreceptor tyrosine-based activation motifs (ITAMs) of the TCR zeta chain through its two src-homology 2 (SH2) domains results in its activation coupled to phosphorylation on multiple tyrosine residues, mediated by Src kinases including Lck as well as by autophosphorylation. |
| GO:0005515 protein binding | IPI PMID:10752619 Alternative modes of binding of proteins with tandem SH2 dom... | MODIFY | Summary: ITC of ZAP70 tandem SH2 domains binding a zeta ITAM phosphopeptide. Reason: The interaction is the SH2-domain-mediated binding of ZAP70 to doubly phosphorylated ITAM tyrosines of the TCR zeta chain (CD247) / CD3 chains; this is captured informatively by phosphotyrosine residue binding (GO:0001784). Proposed replacements: phosphotyrosine residue binding Supporting Evidence: PMID:10752619 In the case of the SH2 domains from ZAP70, they interact with a stoichiometry of unity |
| GO:0005515 protein binding | IPI PMID:11855827 Phosphorylation of the N-terminal and C-terminal CD3-epsilon... | MODIFY | Summary: ZAP-70 associates with the diphosphorylated CD3 epsilon ITAM. Reason: The interaction is the SH2-domain-mediated binding of ZAP70 to doubly phosphorylated ITAM tyrosines of the TCR zeta chain (CD247) / CD3 chains; this is captured informatively by phosphotyrosine residue binding (GO:0001784). Proposed replacements: phosphotyrosine residue binding Supporting Evidence: PMID:11855827 phenylalanine substitution at the N-terminal tyrosine residue of the CD3-epsilon-ITAM abolished signal transduction functions of this ITAM, including phosphorylation at the C-terminal ITAM tyrosine, and its association with ZAP-70. |
| GO:0005515 protein binding | IPI PMID:11891219 A novel Src homology 2 domain-containing molecule, Src-like ... | REMOVE | Summary: SLAP-2 (SLA2) associates with ZAP70 after TCR activation. Reason: Generic protein binding is uninformative. Removing it does not dispute the reported interaction; SLA2 is a negative regulator that associates with ZAP70 and zeta, and the abstract offers no informative ZAP70 molecular function beyond association. Supporting Evidence: PMID:11891219 SLAP-2 interacts with Cbl in vivo in a phosphorylation independent manner and with ZAP-70 and T cell receptor zeta chain upon T cell receptor activation. |
| GO:0005515 protein binding | IPI PMID:12051764 SPAP2, an Ig family receptor containing both ITIMs and ITAMs... | MODIFY | Summary: Tyrosine-phosphorylated FCRL3 (SPAP2) motifs associate with the SH2 domains of Syk and ZAP70. Reason: The interaction is phosphorylation-dependent SH2 binding of ZAP70 to phosphotyrosine motifs of FCRL3; phosphotyrosine residue binding (GO:0001784) is the informative MF. Physiological relevance of FCRL3-ZAP70 in T cells is unclear, so this is not core evidence. Proposed replacements: phosphotyrosine residue binding Supporting Evidence: PMID:12051764 Tyrosine-phosphorylated SPAP2 is specifically associated with SH2 domain-containing tyrosine kinases Syk and Zap70 |
| GO:0005515 protein binding | IPI PMID:12359715 Molecular cloning of a novel gene encoding a membrane-associ... | REMOVE | Summary: LAX is phosphorylated by Src/Syk-family kinases; interaction with ZAP70 reported. Reason: Generic protein binding is uninformative. Removing it does not dispute the reported interaction; the LAX relationship is most plausibly kinase-substrate, which is captured by the kinase activity terms. Supporting Evidence: PMID:12359715 Upon stimulation via the B or T cell receptors, LAX is rapidly phosphorylated by Src and Syk family tyrosine kinases and interacts with Grb2, Gads, and p85. |
| GO:0005515 protein binding | IPI PMID:12646565 Synergistic assembly of linker for activation of T cells sig... | REMOVE | Summary: LAT signaling complexes in TCR plasma membrane domains; ZAP70 detected with LAT. Reason: Generic protein binding is uninformative. Removing it does not dispute the reported interaction; LAT is the principal ZAP70 substrate; that relationship is captured by the kinase activity annotations and core_functions substrates. Supporting Evidence: PMID:12646565 Transmembrane adaptor molecule LAT (linker for activation of T cells) forms a central scaffold for signaling protein complexes that accumulate in the vicinity of activated T cell antigen receptors (TCR). |
| GO:0005515 protein binding | IPI PMID:15832366 Peptide microarrays for the detection of molecular interacti... | MODIFY | Summary: Peptide microarray detection of ZAP70 tandem SH2 binding a bis-phosphotyrosine TCR motif. Reason: The interaction is the SH2-domain-mediated binding of ZAP70 to doubly phosphorylated ITAM tyrosines of the TCR zeta chain (CD247) / CD3 chains; this is captured informatively by phosphotyrosine residue binding (GO:0001784). Proposed replacements: phosphotyrosine residue binding Supporting Evidence: PMID:15832366 The method is exemplified for the lymphocyte-specific tyrosine kinase 70 kDa zeta-associated protein binding to a bis-phosphotyrosine-motif of the activated T-cell receptor via its tandem SH2 domain. |
| GO:0005515 protein binding | IPI PMID:16273093 A quantitative protein interaction network for the ErbB rece... | REMOVE | Summary: High-throughput SH2/PTB domain microarray against ErbB receptor phosphopeptides (EGFR). Reason: Generic protein binding is uninformative. Removing it does not dispute the reported interaction; binding of an isolated ZAP70 SH2 construct to EGFR phosphopeptides in an in vitro domain screen has no demonstrated physiological role; ZAP70 is not expressed alongside EGFR signaling in its native cell types. Supporting Evidence: PMID:16273093 we use protein microarrays comprising virtually every Src homology 2 (SH2) and phosphotyrosine binding (PTB) domain encoded in the human genome |
| GO:0005515 protein binding | IPI PMID:16461343 Identification of substrates of human protein-tyrosine phosp... | REMOVE | Summary: PTPN22 substrate-trap study; LCK co-identified with ZAP70. Reason: Generic protein binding is uninformative. Removing it does not dispute the reported interaction; in this study ZAP70 and LCK are both PTPN22 substrates; the co-association is uninformative about ZAP70 function. Supporting Evidence: PMID:16461343 Native PTPN22 dephosphorylated Lck and Zap70 at their activating tyrosine residues Tyr-394 and Tyr-493, respectively |
| GO:0005515 protein binding | IPI PMID:16461343 Identification of substrates of human protein-tyrosine phosp... | REMOVE | Summary: PTPN22 substrate-trapping mutant binds and PTPN22 dephosphorylates ZAP70 pY493. Reason: Generic protein binding is uninformative. Removing it does not dispute the reported interaction; ZAP70 is the substrate of the phosphatase here; this is regulation of ZAP70, not a ZAP70 activity. Supporting Evidence: PMID:16461343 Native PTPN22 dephosphorylated Lck and Zap70 at their activating tyrosine residues Tyr-394 and Tyr-493, respectively |
| GO:0005515 protein binding | IPI PMID:19843936 FCRL3, an autoimmune susceptibility gene, has inhibitory pot... | REMOVE | Summary: FCRL3 inhibitory signaling in B cells; ZAP70 association reported. Reason: Generic protein binding is uninformative. Removing it does not dispute the reported interaction; the cached abstract describes FCRL3 association with SH2 phosphatases and does not describe a ZAP70-specific function that could replace the generic term. Supporting Evidence: PMID:19843936 further supported by strong associations of SH-2 domain-containing phosphatases with the following phosphotyrosine motifs |
| GO:0005515 protein binding | IPI PMID:21957439 The transmembrane adaptor protein SIT inhibits TCR-mediated ... | REMOVE | Summary: Co-immunoprecipitation of ZAP70 with TCR zeta in SIT-knockdown T cells. Reason: Generic protein binding is uninformative. Removing it does not dispute the reported interaction; the experiment uses TCRzeta-ZAP70 co-association as a readout of proximal signaling rather than characterising the binding; the informative ITAM-binding function is captured by GO:0001784 from dedicated binding studies. Supporting Evidence: PMID:21957439 analysis of immunoprecipitated TCRΞΆ showed that the association with ZAP-70 was also increased in SIT dim T cells |
| GO:0005515 protein binding | IPI PMID:22266821 Structural basis for autoinhibition and phosphorylation-depe... | REMOVE | Summary: CBL TKBD bound to a ZAP-70 phosphopeptide (pY292) in crystal structures. Reason: Generic protein binding is uninformative. Removing it does not dispute the reported interaction; ZAP70 pY292 is a substrate-recognition motif for the CBL E3 ligase; the binding function is CBL's (phosphotyrosine binding by the TKBD), not ZAP70's. Supporting Evidence: PMID:22266821 The TKBD mediates substrate specificity by binding to proteins containing phosphotyrosine motifs commonly found in RTKs or tyrosine kinases such as Zap-70 kinase |
| GO:0005515 protein binding | IPI PMID:23460737 GRB2-mediated recruitment of THEMIS to LAT is essential for ... | REMOVE | Summary: ZAP70 and LCK phosphorylate THEMIS. Reason: Generic protein binding is uninformative. Removing it does not dispute the reported interaction; the relationship is kinase-substrate and is captured by the tyrosine kinase activity annotations. Supporting Evidence: PMID:23460737 We deduce that THEMIS can be a substrate of both Lck and ZAP70. |
| GO:0005515 protein binding | IPI PMID:24256567 Insights into the suppressor of T-cell receptor (TCR) signal... | REMOVE | Summary: Sts-1 (UBASH3B) substrate-trapping mutants capture phosphorylated ZAP70. Reason: Generic protein binding is uninformative. Removing it does not dispute the reported interaction; ZAP70 is the phosphatase substrate; no ZAP70 activity is implied. Supporting Evidence: PMID:24256567 Sts-1 substrate-trapping mutants isolated tyrosine-phosphorylated Zap-70 from lysates of activated T cells, validating Zap-70 as a possible substrate for Sts-1 |
| GO:0005515 protein binding | IPI PMID:24658140 The mammalian-membrane two-hybrid assay (MaMTH) for probing ... | REMOVE | Summary: MaMTH membrane two-hybrid screen with EGFR. Reason: Generic protein binding is uninformative. Removing it does not dispute the reported interaction; a high-throughput EGFR interactor screen gives no evidence of a physiological ZAP70 function. Supporting Evidence: PMID:24658140 We present a split ubiquitin-based method for detection of integral membrane protein-protein interactions (PPIs) in human cells, termed mammalian-membrane two-hybrid assay (MaMTH). |
| GO:0005515 protein binding | IPI PMID:24728074 Enhanced prediction of Src homology 2 (SH2) domain binding p... | REMOVE | Summary: Fluorescence-polarization SH2 domain interactome with MET phosphopeptides. Reason: Generic protein binding is uninformative. Removing it does not dispute the reported interaction; isolated SH2 domain binding to MET-derived phosphopeptides in vitro; no physiological relevance to ZAP70 in lymphocytes. Supporting Evidence: PMID:24728074 We employed a high throughput interaction assay system to empirically determine the affinity between 93 human SH2 domains and phosphopeptides abstracted from several receptor tyrosine kinases and signaling proteins. |
| GO:0005515 protein binding | IPI PMID:24728074 Enhanced prediction of Src homology 2 (SH2) domain binding p... | REMOVE | Summary: Fluorescence-polarization SH2 domain interactome with KIT phosphopeptides. Reason: Generic protein binding is uninformative. Removing it does not dispute the reported interaction; isolated SH2 domain binding to KIT-derived phosphopeptides in vitro; no physiological relevance to ZAP70 in lymphocytes. Supporting Evidence: PMID:24728074 We employed a high throughput interaction assay system to empirically determine the affinity between 93 human SH2 domains and phosphopeptides abstracted from several receptor tyrosine kinases and signaling proteins. |
| GO:0005515 protein binding | IPI PMID:26783323 A novel human autoimmune syndrome caused by combined hypomor... | MODIFY | Summary: ZAP70 C-SH2 mutant R192W shows reduced binding to phosphorylated zeta chain. Reason: The interaction is the SH2-domain-mediated binding of ZAP70 to doubly phosphorylated ITAM tyrosines of the TCR zeta chain (CD247) / CD3 chains; this is captured informatively by phosphotyrosine residue binding (GO:0001784). Proposed replacements: phosphotyrosine residue binding Supporting Evidence: PMID:26783323 Mutation R192W in the C-SH2 domain exhibited reduced binding to phosphorylated ΞΆ-chain, whereas mutation R360P in the N lobe of the catalytic domain disrupted an autoinhibitory mechanism, producing a weakly hyperactive ZAP-70 protein. PMID:37313400 the impact of these mutations on binding to the phosphate moiety of the phosphorylated TCR-ΞΆ chain ITAMs |
| GO:0005515 protein binding | IPI PMID:31980649 Extensive rewiring of the EGFR network in colorectal cancer ... | REMOVE | Summary: EGFR network PPI mapping in KRAS-mutant colorectal cancer cells. Reason: Generic protein binding is uninformative. Removing it does not dispute the reported interaction; a large-scale PPI map in colorectal cancer cells, where ZAP70 has no established role, gives no informative ZAP70 function. Supporting Evidence: PMID:31980649 Mapping >6000 PPIs shows that this network is extensively rewired in cells expressing transforming levels of KRASG13D (mtKRAS). |
| GO:0005515 protein binding | IPI PMID:7509083 Sequential interactions of the TCR with two distinct cytopla... | MODIFY | Summary: Lck-phosphorylated ITAMs recruit ZAP-70 through both SH2 domains. Reason: The interaction is the SH2-domain-mediated binding of ZAP70 to doubly phosphorylated ITAM tyrosines of the TCR zeta chain (CD247) / CD3 chains; this is captured informatively by phosphotyrosine residue binding (GO:0001784). Proposed replacements: phosphotyrosine residue binding Supporting Evidence: PMID:7509083 This phosphorylation leads to the recruitment of a second cytoplasmic PTK, ZAP-70, through both of the ZAP-70 Src homology 2 domains and its phosphorylation. |
| GO:0005515 protein binding | IPI PMID:7528772 ZAP-70 binding specificity to T cell receptor tyrosine-based... | MODIFY | Summary: Tandem ZAP-70 SH2 domains bind doubly phosphorylated zeta/CD3 epsilon TAM peptides. Reason: The interaction is the SH2-domain-mediated binding of ZAP70 to doubly phosphorylated ITAM tyrosines of the TCR zeta chain (CD247) / CD3 chains; this is captured informatively by phosphotyrosine residue binding (GO:0001784). Proposed replacements: phosphotyrosine residue binding Supporting Evidence: PMID:7528772 Direct binding studies demonstrated that the tandem ZAP-70 SH2 domains bind phosphorylated, but not nonphosphorylated, TCR zeta cyt. |
| GO:0005515 protein binding | IPI PMID:7761456 Analysis of the interaction of ZAP-70 and syk protein-tyrosi... | MODIFY | Summary: SPR kinetics of ZAP-70 SH2 domains binding the phosphorylated CD3 epsilon ITAM. Reason: The interaction is the SH2-domain-mediated binding of ZAP70 to doubly phosphorylated ITAM tyrosines of the TCR zeta chain (CD247) / CD3 chains; this is captured informatively by phosphotyrosine residue binding (GO:0001784). Proposed replacements: phosphotyrosine residue binding Supporting Evidence: PMID:7761456 The association rate and equilibrium binding constants for the ZAP-70 and syk SH2 domains were determined for the CD3 epsilon ITAM. |
| GO:0005515 protein binding | IPI PMID:8648092 Human and mouse killer-cell inhibitory receptors recruit PTP... | REMOVE | Summary: KIR/ITIM phosphatase recruitment study; ZAP70-zeta interaction presumably used in the full text. Reason: Generic protein binding is uninformative. Removing it does not dispute the reported interaction; the cached abstract concerns KIR recruitment of PTP1C/PTP1D and gives no ZAP70-specific information to support a more informative term; the ZAP70-zeta ITAM interaction is captured by GO:0001784 from other papers. Supporting Evidence: PMID:8648092 NK cells express cell surface receptors for MHC class I proteins (KIR). |
| GO:0005515 protein binding | IPI PMID:8901551 Mechanism of activation for Zap-70 catalytic activity. | MODIFY | Summary: Binding of dimeric phosphorylated zeta via SH2 domains stimulates ZAP70 catalytic activity. Reason: The interaction is the SH2-domain-mediated binding of ZAP70 to doubly phosphorylated ITAM tyrosines of the TCR zeta chain (CD247) / CD3 chains; this is captured informatively by phosphotyrosine residue binding (GO:0001784). Proposed replacements: phosphotyrosine residue binding Supporting Evidence: PMID:8901551 The increase in Zap-70 activity was SH2 mediated and was inhibited by phenylphosphate, Zap-70 SH2, and an antibody specific for Zap-70 SH2 domains. |
| GO:0005515 protein binding | IPI PMID:9185620 Interaction between the SH2 domains of ZAP-70 and the tyrosi... | MODIFY | Summary: ZAP-70 SH2 domains bind the zeta ITAM1 phosphopeptide (BIAcore). Reason: The interaction is the SH2-domain-mediated binding of ZAP70 to doubly phosphorylated ITAM tyrosines of the TCR zeta chain (CD247) / CD3 chains; this is captured informatively by phosphotyrosine residue binding (GO:0001784). Proposed replacements: phosphotyrosine residue binding Supporting Evidence: PMID:9185620 One of the key steps involved in T-cell activation is binding of the tyrosine kinase ZAP-70 via its two SH2 domains to peptide segments termed tyrosine-based activation motifs (ITAM) |
| GO:0005524 ATP binding | IEA GO_REF:0000120 | ACCEPT | Summary: ATP binding by the kinase domain (IEA). Reason: ATP binding is intrinsic to the catalytic kinase domain; structure shows the ATP-binding site occupied by staurosporine. Supporting Evidence: PMID:15292186 The unique features of the ATP-binding site, identified by structural and sequence comparison with other kinases, will be useful in the design of ZAP-70-selective inhibitors. |
| GO:0005524 ATP binding | NAS PMID:1423621 ZAP-70: a 70 kd protein-tyrosine kinase that associates with... | ACCEPT | Summary: ATP binding (NAS, original cloning paper). Reason: Consistent with ZAP70 being an active protein tyrosine kinase with a canonical ATP-binding site. Supporting Evidence: PMID:1423621 ZAP-70 represents a novel PTK and is expressed in T and natural killer cells. PMID:15292186 The unique features of the ATP-binding site, identified by structural and sequence comparison with other kinases, will be useful in the design of ZAP-70-selective inhibitors. |
| GO:0005737 cytoplasm | IDA PMID:9489702 LAT: the ZAP-70 tyrosine kinase substrate that links T cell ... | ACCEPT | Summary: ZAP70 is active in the cytoplasm, phosphorylating LAT. Reason: ZAP70 is cytoplasmic in resting T cells and translocates to the plasma membrane on TCR engagement. Supporting Evidence: file:human/ZAP70/ZAP70-uniprot.txt In quiescent T-lymphocytes, it is cytoplasmic. Upon TCR activation, it is recruited at the plasma membrane by interacting with CD247/CD3Z. PMID:9813084 Photobleaching techniques revealed that ZAP-70 GFP has decreased mobility at the plasma membrane, in contrast to its rapid mobility in the cytosol and nucleus. |
| GO:0005737 cytoplasm | IEA GO_REF:0000120 | ACCEPT | Summary: Cytoplasm (IEA). Reason: ZAP70 is cytoplasmic in resting T cells and translocates to the plasma membrane on TCR engagement. Supporting Evidence: file:human/ZAP70/ZAP70-uniprot.txt In quiescent T-lymphocytes, it is cytoplasmic. Upon TCR activation, it is recruited at the plasma membrane by interacting with CD247/CD3Z. |
| GO:0005737 cytoplasm | TAS PMID:12359715 Molecular cloning of a novel gene encoding a membrane-associ... | ACCEPT | Summary: Cytoplasm (TAS, LAX paper). Reason: ZAP70 is cytoplasmic in resting T cells and translocates to the plasma membrane on TCR engagement. The cited LAX paper is a weak source for this, but the location is well established. Supporting Evidence: file:human/ZAP70/ZAP70-uniprot.txt In quiescent T-lymphocytes, it is cytoplasmic. Upon TCR activation, it is recruited at the plasma membrane by interacting with CD247/CD3Z. |
| GO:0005829 cytosol | IEA GO_REF:0000120 | ACCEPT | Summary: ZAP70 is a soluble cytosolic kinase in resting T cells. Reason: ZAP70 is cytoplasmic in resting T cells and translocates to the plasma membrane on TCR engagement. Supporting Evidence: file:human/ZAP70/ZAP70-uniprot.txt In quiescent T-lymphocytes, it is cytoplasmic. Upon TCR activation, it is recruited at the plasma membrane by interacting with CD247/CD3Z. PMID:9813084 Photobleaching techniques revealed that ZAP-70 GFP has decreased mobility at the plasma membrane, in contrast to its rapid mobility in the cytosol and nucleus. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-202168 | ACCEPT | Summary: ZAP70 is a soluble cytosolic kinase in resting T cells (Reactome R-HSA-202168). Reason: ZAP70 is cytoplasmic in resting T cells and translocates to the plasma membrane on TCR engagement. Supporting Evidence: Reactome:R-HSA-202168 This site has shown to be a positive regulatory site required for ZAP-70 kinase activity and is phosphorylated by Lck. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-202174 | ACCEPT | Summary: ZAP70 is a soluble cytosolic kinase in resting T cells (Reactome R-HSA-202174). Reason: ZAP70 is cytoplasmic in resting T cells and translocates to the plasma membrane on TCR engagement. Supporting Evidence: Reactome:R-HSA-202174 Activated ZAP-70 phosphorylates T-cell-specific adaptors, such as LAT and SLP-76 |
| GO:0005829 cytosol | TAS Reactome:R-HSA-202216 | ACCEPT | Summary: ZAP70 is a soluble cytosolic kinase in resting T cells (Reactome R-HSA-202216). Reason: ZAP70 is cytoplasmic in resting T cells and translocates to the plasma membrane on TCR engagement. Supporting Evidence: Reactome:R-HSA-202216 These tyrosine residues are phosphorylated by tyrosine kinase ZAP-70 |
| GO:0005829 cytosol | TAS Reactome:R-HSA-202245 | ACCEPT | Summary: ZAP70 is a soluble cytosolic kinase in resting T cells (Reactome R-HSA-202245). Reason: ZAP70 is cytoplasmic in resting T cells and translocates to the plasma membrane on TCR engagement. Supporting Evidence: Reactome:R-HSA-202245 These tyrosine residues are phosphorylated by the activated ZAP-70 upon TCR/CD3 complex engagement. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-202248 | ACCEPT | Summary: ZAP70 is a soluble cytosolic kinase in resting T cells (Reactome R-HSA-202248). Reason: ZAP70 is cytoplasmic in resting T cells and translocates to the plasma membrane on TCR engagement. Supporting Evidence: Reactome:R-HSA-202248 The phosphorylation of the tyrosine residues and the activation of PLC-gamma1 is mediated by both Syk tyrosine kinase ZAP-70 and Tec kinase ITK. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-202344 | ACCEPT | Summary: ZAP70 is a soluble cytosolic kinase in resting T cells (Reactome R-HSA-202344). Reason: ZAP70 is cytoplasmic in resting T cells and translocates to the plasma membrane on TCR engagement. Supporting Evidence: Reactome:R-HSA-202344 The dually phosphorylated ITAMs provide a high-affinity docking site for the tandem SH2-domains of the ZAP-70. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-8855381 | ACCEPT | Summary: ZAP70 is a soluble cytosolic kinase in resting T cells (Reactome R-HSA-8855381). Reason: ZAP70 is cytoplasmic in resting T cells and translocates to the plasma membrane on TCR engagement. Supporting Evidence: Reactome:R-HSA-8855381 Protein tyrosine phosphatase PTPN22 (LYP, PEP) dephosphorylates ZAP70 adaptor protein on tyrosine residue Y493, resulting in reduced activation of ZAP70. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9018758 | ACCEPT | Summary: ZAP70 is a soluble cytosolic kinase in resting T cells (Reactome R-HSA-9018758). Reason: ZAP70 is cytoplasmic in resting T cells and translocates to the plasma membrane on TCR engagement. Supporting Evidence: Reactome:R-HSA-9018758 RHOH plays an important role in development of T lymphocytes and binds to several kinases involved in T lymphocyte activation |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9851133 | ACCEPT | Summary: ZAP70 is a soluble cytosolic kinase in resting T cells (Reactome R-HSA-9851133). Reason: ZAP70 is cytoplasmic in resting T cells and translocates to the plasma membrane on TCR engagement. Supporting Evidence: Reactome:R-HSA-9851133 Expression of ZAP70 and other components of the TCR signaling pathway such as LAT, SLP76 and CD3 are downregulated by NPM1-ALK in a kinase dependent fashion. |
| GO:0005886 plasma membrane | IBA GO_REF:0000033 | ACCEPT | Summary: Plasma membrane (IBA). Reason: ZAP70 is a peripheral plasma membrane protein when docked on phosphorylated CD3/zeta ITAMs of the engaged TCR, which is where it acts. Supporting Evidence: PMID:9813084 After antigenic stimulation, ZAP-70 rapidly associates with T cell receptor (TCR) subunits. file:human/ZAP70/ZAP70-uniprot.txt In quiescent T-lymphocytes, it is cytoplasmic. Upon TCR activation, it is recruited at the plasma membrane by interacting with CD247/CD3Z. |
| GO:0005886 plasma membrane | IDA PMID:12150984 Calpain II colocalizes with detergent-insoluble rafts on hum... | ACCEPT | Summary: Plasma membrane (IDA; calpain/raft study in human and Jurkat T cells). Reason: ZAP70 is a peripheral plasma membrane protein when docked on phosphorylated CD3/zeta ITAMs of the engaged TCR, which is where it acts. The cached abstract does not mention ZAP70 (full text unavailable); deferring to the curator since the location is well established. Supporting Evidence: PMID:12150984 we report the novel observation that calpain II, but not calpain I, associates with membrane lipid rafts on human peripheral blood T-cells and Jurkat cells file:human/ZAP70/ZAP70-uniprot.txt In quiescent T-lymphocytes, it is cytoplasmic. Upon TCR activation, it is recruited at the plasma membrane by interacting with CD247/CD3Z. |
| GO:0005886 plasma membrane | IDA PMID:9813084 ZAP-70 association with T cell receptor zeta (TCRzeta): fluo... | ACCEPT | Summary: ZAP-70-GFP translocates to and is retained at the plasma membrane via TCR zeta after stimulation. Reason: ZAP70 is a peripheral plasma membrane protein when docked on phosphorylated CD3/zeta ITAMs of the engaged TCR, which is where it acts. Supporting Evidence: PMID:9813084 After antigenic stimulation, ZAP-70 rapidly associates with T cell receptor (TCR) subunits. PMID:9813084 Photobleaching techniques revealed that ZAP-70 GFP has decreased mobility at the plasma membrane, in contrast to its rapid mobility in the cytosol and nucleus. |
| GO:0005886 plasma membrane | IEA GO_REF:0000120 | ACCEPT | Summary: Plasma membrane (IEA). Reason: ZAP70 is a peripheral plasma membrane protein when docked on phosphorylated CD3/zeta ITAMs of the engaged TCR, which is where it acts. Supporting Evidence: file:human/ZAP70/ZAP70-uniprot.txt In quiescent T-lymphocytes, it is cytoplasmic. Upon TCR activation, it is recruited at the plasma membrane by interacting with CD247/CD3Z. |
| GO:0005886 plasma membrane | TAS PMID:20135127 ZAP70: a master regulator of adaptive immunity. | ACCEPT | Summary: Plasma membrane (TAS review). Reason: ZAP70 is a peripheral plasma membrane protein when docked on phosphorylated CD3/zeta ITAMs of the engaged TCR, which is where it acts. Supporting Evidence: file:human/ZAP70/ZAP70-uniprot.txt In quiescent T-lymphocytes, it is cytoplasmic. Upon TCR activation, it is recruited at the plasma membrane by interacting with CD247/CD3Z. |
| GO:0005911 cell-cell junction | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Cell-cell junction (IEA from mouse ortholog). Reason: Likely derived from ZAP70 localization at the T cell-APC contact (immunological synapse); not wrong, but immunological synapse (GO:0001772) is the informative location. Supporting Evidence: file:human/ZAP70/ZAP70-uniprot.txt Colocalizes together with RHOH in the immunological synapse. |
| GO:0006468 protein phosphorylation | IDA PMID:12447358 Tyrosine phosphorylation of VHR phosphatase by ZAP-70. | ACCEPT | Summary: ZAP70 phosphorylates VHR on Tyr138. Reason: ZAP70 directly performs protein (tyrosine) phosphorylation; this process term follows from its catalytic activity. Supporting Evidence: PMID:12447358 is phosphorylated at Y138 by ZAP-70 |
| GO:0006468 protein phosphorylation | NAS PMID:1423621 ZAP-70: a 70 kd protein-tyrosine kinase that associates with... | ACCEPT | Summary: Protein phosphorylation (NAS). Reason: ZAP70 is a protein tyrosine kinase; general but correct. Supporting Evidence: PMID:1423621 ZAP-70 represents a novel PTK and is expressed in T and natural killer cells. |
| GO:0006955 immune response | IDA PMID:1423621 ZAP-70: a 70 kd protein-tyrosine kinase that associates with... | KEEP AS NON CORE | Summary: Immune response (IDA, original ZAP-70 characterization). Reason: Very broad; the specific process ZAP70 participates in is TCR signaling (GO:0050852), which is already annotated. Supporting Evidence: PMID:1423621 ZAP-70 represents a novel PTK and is expressed in T and natural killer cells. PMID:1423621 tyrosine phosphorylation and association of ZAP-70 with zeta require the presence of src family PTKs |
| GO:0007159 leukocyte cell-cell adhesion | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: Leukocyte cell-cell adhesion (IEA, ARBA). Reason: ZAP70 contributes to TCR- and chemokine-induced integrin inside-out signaling (e.g. VAV1 phosphorylation in a talin/integrin beta1 complex), so a role in adhesion is plausible, but it is a downstream consequence of its signaling kinase role. Supporting Evidence: PMID:23620790 Complex 5 contains ZAP70, CBAP, integrin Ξ²1 and Vav1, which upon phosphorylation of Vav1 by ZAP70 quickly dissociates from integrin Ξ²1 and transforms into complex 6 (ZAP70/CBAP/pVav1) that can further activate downstream targets like Rac1. |
| GO:0016020 membrane | IEA GO_REF:0000107 | ACCEPT | Summary: Membrane (IEA). Reason: General but correct; ZAP70 is a peripheral membrane protein when recruited to the TCR. Supporting Evidence: file:human/ZAP70/ZAP70-uniprot.txt In quiescent T-lymphocytes, it is cytoplasmic. Upon TCR activation, it is recruited at the plasma membrane by interacting with CD247/CD3Z. |
| GO:0018108 peptidyl-tyrosine phosphorylation | IDA PMID:22732588 Interchangeability of Themis1 and Themis2 in thymocyte devel... | ACCEPT | Summary: Peptidyl-tyrosine phosphorylation (IDA; Themis1/Themis2 thymocyte study). Reason: ZAP70 is a protein tyrosine kinase, so the term is correct for the gene. However, the cited full text reports that ZAP-70 did not phosphorylate Themis1/2 in co-transfection and that Themis1 phosphorylation persisted in ZAP70-deficient P116 cells; the specific evidence from this paper is therefore weak and the annotation is best supported by other references (e.g. PMID:23620790, PMID:12447358). Supporting Evidence: PMID:22732588 Co-transfection experiments in 293T cells demonstrated that Src kinases (Lck or Fyn) but not the ZAP-70 kinase can phosphorylate both Themis1 and Themis2 (Fig 4B). PMID:12447358 is phosphorylated at Y138 by ZAP-70 |
| GO:0018108 peptidyl-tyrosine phosphorylation | IMP PMID:23620790 CBAP functions as a novel component in chemokine-induced ZAP... | ACCEPT | Summary: ZAP70 phosphorylates VAV1 in a CBAP/integrin beta1 complex during chemokine signaling. Reason: Direct role of ZAP70 kinase in tyrosine phosphorylation of a substrate. Supporting Evidence: PMID:23620790 Complex 5 contains ZAP70, CBAP, integrin Ξ²1 and Vav1, which upon phosphorylation of Vav1 by ZAP70 quickly dissociates from integrin Ξ²1 and transforms into complex 6 (ZAP70/CBAP/pVav1) that can further activate downstream targets like Rac1. |
| GO:0030217 T cell differentiation | NAS PMID:8613493 A mutation in zap-70 protein tyrosine kinase results in a se... | KEEP AS NON CORE | Summary: T cell differentiation (NAS; ZAP70-deficient patients lack CD8 SP T cells). Reason: Loss-of-function data establish necessity: ZAP70 TCR signaling is required for thymocyte selection and CD8 T cell development. ZAP70's own work is TCR signal transduction; differentiation is a downstream consequence, so non-core per the necessity-vs-participation rule. Supporting Evidence: PMID:8613493 zap-70 kinase appears to be indispensable for the development of CD8 single-positive T cells as well as for the signal transduction and function of single-positive CD4 T cells |
| GO:0035556 intracellular signal transduction | IEA GO_REF:0000002 | ACCEPT | Summary: Intracellular signal transduction (IEA, InterPro). Reason: General but correct; ZAP70 is a cytoplasmic signaling kinase. The specific term is TCR signaling pathway. Supporting Evidence: PMID:20135127 These studies demonstrated that ZAP70 was indeed at the crossroad of several signalling pathways that control T lymphocyte development and function. |
| GO:0035556 intracellular signal transduction | NAS PMID:1423621 ZAP-70: a 70 kd protein-tyrosine kinase that associates with... | ACCEPT | Summary: Intracellular signal transduction (NAS). Reason: General but correct. Supporting Evidence: PMID:1423621 tyrosine phosphorylation and association of ZAP-70 with zeta require the presence of src family PTKs |
| GO:0042101 T cell receptor complex | IDA PMID:8176201 Differential expression of ZAP-70 and Syk protein tyrosine k... | KEEP AS NON CORE | Summary: ZAP70 associates with the TCR after stimulation (IDA). Reason: ZAP70 is recruited to phosphorylated CD3/zeta ITAMs only after TCR stimulation and is not a stoichiometric structural subunit of the TCR-CD3 complex; the annotation reflects a signaling-induced association, so it is kept but not treated as core. Supporting Evidence: PMID:8176201 Finally, we provide evidence that both ZAP-70 and Syk can associate with the TCR after TCR stimulation. |
| GO:0042101 T cell receptor complex | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: T cell receptor complex (IEA, ARBA). Reason: As for the IDA row: ZAP70 is recruited to, rather than a constitutive subunit of, the TCR complex. Supporting Evidence: PMID:8176201 Finally, we provide evidence that both ZAP-70 and Syk can associate with the TCR after TCR stimulation. |
| GO:0042110 T cell activation | IDA PMID:38614099 ITPRIPL1 binds CD3Ξ΅ to impede TΒ cell activation and enable t... | KEEP AS NON CORE | Summary: ZAP70 phosphorylation used as a readout of T cell activation inhibited by ITPRIPL1 (abstract only). Reason: ZAP70 does contribute to T cell activation as the TCR-proximal kinase, but T cell activation is a broad outcome; the process ZAP70 performs work in is the TCR signaling pathway. Supporting Evidence: PMID:38614099 The binding of ITPRIPL1 extracellular domain to CD3Ξ΅ on T cells significantly decreased calcium influx and ZAP70 phosphorylation, impeding initial T cell activation. |
| GO:0042110 T cell activation | TAS PMID:20135127 ZAP70: a master regulator of adaptive immunity. | KEEP AS NON CORE | Summary: T cell activation (TAS review). Reason: Broad outcome of ZAP70-dependent TCR signaling; see TCR signaling pathway for the core process. Supporting Evidence: PMID:20135127 These studies demonstrated that ZAP70 was indeed at the crossroad of several signalling pathways that control T lymphocyte development and function. |
| GO:0042113 B cell activation | TAS PMID:20135127 ZAP70: a master regulator of adaptive immunity. | MARK AS OVER ANNOTATED | Summary: B cell activation (TAS review). Reason: ZAP70 is expressed at low levels in pro/pre-B cells and in a subset of CLL B cells, but SYK is the dominant BCR kinase; the review abstract only associates ZAP70 expression in CLL B cells with prognosis. A role in normal B cell activation is not well established. A later primary study (PMID:38113463) shows ZAP70 augments a tonic BCR signal in IGHV-unmutated CLL cells, a malignant context that does not establish a role in normal B cell activation. Supporting Evidence: PMID:20135127 Some chronic lymphocytic leukemia B cells were shown to express ZAP70, and this expression was correlated with bad prognosis. PMID:38113463 We, here, provide evidence that ZAP-70 augments CD19, SRC, and AKT-activation only in IGHV-unmutated, but not mutated, CLL indicating existence of a tonic BCR signal modulated by ZAP-70. |
| GO:0045059 positive thymic T cell selection | IDA PMID:7630421 Essential role for ZAP-70 in both positive and negative sele... | KEEP AS NON CORE | Summary: Zap70-/- mice lack CD4 and CD8 SP thymocytes and fail negative selection; human ZAP-70 rescues. Reason: The knockout/rescue data show necessity of ZAP70 for thymic selection; ZAP70 acts by transducing TCR signals that drive selection (qualifier acts_upstream_of_or_within is appropriate). Non-core developmental outcome. Supporting Evidence: PMID:7630421 Here we show that mice lacking ZAP-70 had neither CD4 nor CD8 single-positive T cells, but human ZAP-70 reconstituted both CD4 and CD8 single-positive populations. PMID:7630421 These data suggest that ZAP-70 is a central signalling molecule during thymic selection for CD4 and CD8 lineage. |
| GO:0045059 positive thymic T cell selection | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: Positive thymic T cell selection (IEA, ARBA). Reason: Same as the IDA row: necessity-based developmental outcome of ZAP70 TCR signaling. Supporting Evidence: PMID:7630421 Here we show that mice lacking ZAP-70 had neither CD4 nor CD8 single-positive T cells, but human ZAP-70 reconstituted both CD4 and CD8 single-positive populations. |
| GO:0045121 membrane raft | IDA PMID:12150984 Calpain II colocalizes with detergent-insoluble rafts on hum... | KEEP AS NON CORE | Summary: ZAP70 colocalizes with membrane rafts (IDA, calpain/raft paper; abstract only). Reason: The colocalizes_with qualifier is a weak claim that is plausible for TCR-proximal signaling components; the cached abstract does not mention ZAP70 so the specific data cannot be verified. Deferring to the curator; non-core. Supporting Evidence: PMID:12150984 we report the novel observation that calpain II, but not calpain I, associates with membrane lipid rafts on human peripheral blood T-cells and Jurkat cells |
| GO:0045582 positive regulation of T cell differentiation | IDA PMID:7630421 Essential role for ZAP-70 in both positive and negative sele... | KEEP AS NON CORE | Summary: Positive regulation of T cell differentiation (IDA, Zap70 knockout mice). Reason: Necessity evidence from knockout; ZAP70's direct work is TCR signal transduction, with thymocyte maturation as a downstream consequence. Supporting Evidence: PMID:7630421 Here we show that mice lacking ZAP-70 had neither CD4 nor CD8 single-positive T cells, but human ZAP-70 reconstituted both CD4 and CD8 single-positive populations. |
| GO:0045582 positive regulation of T cell differentiation | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: Positive regulation of T cell differentiation (IEA, ARBA). Reason: As for the IDA row. Supporting Evidence: PMID:7630421 Here we show that mice lacking ZAP-70 had neither CD4 nor CD8 single-positive T cells, but human ZAP-70 reconstituted both CD4 and CD8 single-positive populations. |
| GO:0050852 T cell receptor signaling pathway | IDA PMID:11368773 Mapping the Zap-70 phosphorylation sites on LAT (linker for ... | ACCEPT | Summary: ZAP70 phosphorylates LAT at Y127/Y132/Y171/Y191/Y226, which is sufficient to recruit and activate PLCgamma1, PI3K and VAV. Reason: ZAP70 is a direct participant in the TCR signaling pathway: it is recruited to phospho-ITAMs and phosphorylates LAT and LCP2/SLP-76 to propagate the signal. Core process. Supporting Evidence: PMID:11368773 Zap-70 efficiently phosphorylates LAT on tyrosine residues at positions 226, 191, 171, 132 and 127. PMID:11368773 a direct tyrosine phosphorylation of LAT with activated protein-tyrosine kinase Zap70 is necessary and sufficient for the association and activation of signalling proteins |
| GO:0050852 T cell receptor signaling pathway | IDA PMID:25907557 The Us3 Protein of Herpes Simplex Virus 1 Inhibits T Cell Si... | ACCEPT | Summary: ZAP70 phosphorylation of LAT in TCR signaling (HSV-1 Us3 study). Reason: ZAP70 is a direct participant in the TCR signaling pathway: it is recruited to phospho-ITAMs and phosphorylates LAT and LCP2/SLP-76 to propagate the signal. Core process. Supporting Evidence: PMID:25907557 ZAP-70 phosphorylates the linker for activation of T cells (LAT), which provides docking sites for downstream signaling molecules such as phospholipase C Ξ³1 (PLCΞ³1), growth factor receptor-bound protein 2 (Grb2), and Vav1 |
| GO:0050852 T cell receptor signaling pathway | IDA PMID:38614099 ITPRIPL1 binds CD3Ξ΅ to impede TΒ cell activation and enable t... | ACCEPT | Summary: ZAP70 phosphorylation as part of TCR signaling (ITPRIPL1 study, abstract only). Reason: ZAP70 is a direct participant in the TCR signaling pathway: it is recruited to phospho-ITAMs and phosphorylates LAT and LCP2/SLP-76 to propagate the signal. Core process. Supporting Evidence: PMID:38614099 The binding of ITPRIPL1 extracellular domain to CD3Ξ΅ on T cells significantly decreased calcium influx and ZAP70 phosphorylation, impeding initial T cell activation. |
| GO:0050852 T cell receptor signaling pathway | IDA PMID:9489702 LAT: the ZAP-70 tyrosine kinase substrate that links T cell ... | ACCEPT | Summary: LAT is the ZAP-70 substrate linking the TCR to downstream activation. Reason: ZAP70 is a direct participant in the TCR signaling pathway: it is recruited to phospho-ITAMs and phosphorylates LAT and LCP2/SLP-76 to propagate the signal. Core process. Supporting Evidence: PMID:9489702 We show that this protein is phosphorylated by ZAP-70/Syk protein tyrosine kinases leading to recruitment of multiple signaling molecules. |
| GO:0050852 T cell receptor signaling pathway | IEA GO_REF:0000120 | ACCEPT | Summary: TCR signaling pathway (IEA). Reason: ZAP70 is a direct participant in the TCR signaling pathway: it is recruited to phospho-ITAMs and phosphorylates LAT and LCP2/SLP-76 to propagate the signal. Core process. Supporting Evidence: PMID:7509083 This phosphorylation leads to the recruitment of a second cytoplasmic PTK, ZAP-70, through both of the ZAP-70 Src homology 2 domains and its phosphorylation. |
| GO:0050852 T cell receptor signaling pathway | TAS PMID:20135127 ZAP70: a master regulator of adaptive immunity. | ACCEPT | Summary: TCR signaling pathway (TAS review). Reason: ZAP70 is a direct participant in the TCR signaling pathway: it is recruited to phospho-ITAMs and phosphorylates LAT and LCP2/SLP-76 to propagate the signal. Core process. Supporting Evidence: PMID:20135127 These studies demonstrated that ZAP70 was indeed at the crossroad of several signalling pathways that control T lymphocyte development and function. |
| GO:0050852 T cell receptor signaling pathway | TAS Reactome:R-HSA-202403 | ACCEPT | Summary: Reactome TCR signaling pathway. Reason: ZAP70 is a direct participant in the TCR signaling pathway: it is recruited to phospho-ITAMs and phosphorylates LAT and LCP2/SLP-76 to propagate the signal. Core process. Supporting Evidence: Reactome:R-HSA-202403 Members of the Src kinases (Lck), Syk kinases (ZAP-70), Tec (Itk) and Csk families of nonreceptor PTKs play a crucial role in T cell activation. |
| GO:0050900 leukocyte migration | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: Leukocyte migration (IEA, ARBA). Reason: ZAP70 kinase activity contributes to CXCL12-induced T cell migration via VAV1 phosphorylation, but migration is a downstream, non-core role. Supporting Evidence: PMID:23620790 In a leukemia cell line and human peripheral blood, CXCL12-induced tyrosine phosphorylation of ZAP70 and Vav1 is essential for cell migration |
| GO:0070489 T cell aggregation | TAS PMID:20135127 ZAP70: a master regulator of adaptive immunity. | KEEP AS NON CORE | Summary: T cell aggregation (TAS review). Reason: Homotypic T cell aggregation reflects TCR/integrin-dependent adhesion downstream of ZAP70 signaling; the review abstract does not detail it. Plausible but non-core. Supporting Evidence: PMID:20135127 These studies demonstrated that ZAP70 was indeed at the crossroad of several signalling pathways that control T lymphocyte development and function. |
| GO:0072678 T cell migration | TAS PMID:20135127 ZAP70: a master regulator of adaptive immunity. | KEEP AS NON CORE | Summary: T cell migration (TAS review). Reason: ZAP70 regulates motility of mature T cells (e.g. chemokine-induced migration), a downstream non-core role. Supporting Evidence: PMID:20135127 These studies demonstrated that ZAP70 was indeed at the crossroad of several signalling pathways that control T lymphocyte development and function. PMID:23620790 In a leukemia cell line and human peripheral blood, CXCL12-induced tyrosine phosphorylation of ZAP70 and Vav1 is essential for cell migration |
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Download this section (compressed HTML)Q: Should ZAP70 carry a term for its recruitment to the TCR-CD3 complex (e.g. a 'part_of T cell receptor complex' only in the activated state), or is phosphotyrosine residue binding plus TCR signaling pathway sufficient to capture it?
Q: Which of the many reported ZAP70 substrates beyond LAT and LCP2 (VAV1, DUSP3/VHR, THEMIS) are physiologically relevant in primary T cells, given conflicting reports (THEMIS phosphorylated by ZAP70 in PMID:23460737 but only by Lck/Fyn and not ZAP70 in PMID:22732588), and given that ZAP70 cannot phosphorylate ITAMs and selects acidic-flanked tyrosines (PMID:27700984)? Does the THEMIS sequence context around its phosphosites fit the ZAP70 electrostatic filter?
Q: Does ZAP70 have a non-redundant role in normal B cell development or activation, or is its B-lineage expression (pre-B, CLL) functionally minor relative to SYK? In IGHV-unmutated CLL it augments tonic BCR and CCR7 signaling (PMID:38113463); is this kinase-dependent or a scaffolding effect?
Q: How much does ZAP70 autophosphorylation contribute to its activation in cells? Secondary summaries describe autophosphorylation of regulatory tyrosines, whereas biochemical work reports that ZAP70 autophosphorylates poorly and depends on LCK for activation-loop Y493 phosphorylation (PMID:27700984).
Q: Is cyclophilin A binding to interdomain B (PMID:36495335) a physiological brake on ZAP70 catalytic activity in human T cells, and does it contribute to the immunosuppressive effect of cyclosporin A independently of calcineurin?
Experiment: Phosphoproteomics in primary human T cells with an analog-sensitive ZAP70 allele (chemical genetics) to define direct ZAP70 substrates distinct from LCK/ITK substrates.
Experiment: In vitro kinase assays with purified active ZAP70 (with and without LCK priming) on THEMIS peptides and full-length THEMIS, plus phosphosite mapping in ZAP70-deficient versus reconstituted T cells, to resolve whether THEMIS is a direct ZAP70 substrate.
Experiment: Conditional ZAP70 deletion in mature peripheral B cells or CLL models to test whether ZAP70 kinase activity (versus scaffolding) contributes to BCR signaling.
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