CSK (C-terminal Src kinase) is a cytosolic non-receptor protein tyrosine kinase built from an SH3 domain, an SH2 domain and a kinase domain, lacking both a membrane-anchoring acylation signal and an activation-loop autophosphorylation site. Its main substrates are the C-terminal regulatory tyrosines of Src-family kinases (SRC, LCK, FYN, LYN, YES1, HCK); phosphorylation of this tail lets the kinase's own SH2 domain bind it intramolecularly, locking the kinase in an inactive conformation. Substrate selection relies on a docking interface between the two kinase domains rather than the conventional peptide-binding groove. CSK is recruited from the cytosol to membranes and lipid rafts by SH2 binding to tyrosine-phosphorylated adaptors and receptors (PAG/Cbp, SCIMP, activated IGF-1R/insulin receptor), and its SH3 domain binds the phosphatase PTPN22 (PEP), coordinating Src-family kinase inactivation. Through these activities CSK restrains T- and B-cell antigen receptor, Fc receptor and growth-factor signalling. Csk orthologs are present in choanoflagellates and other unicellular holozoans, where they phosphorylate the Src C-terminal tail; whether that phosphorylation was already strongly inhibitory before animals is disputed, while the adaptor-based recruitment and immune-signalling roles are animal-specific contexts.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0004672 protein kinase activity | IEA GO_REF:0000002 | ACCEPT | Summary: Broad InterPro-based kinase term; correct but less specific than the tyrosine kinase terms also on this gene. Reason: CSK is a catalytically active protein kinase (tyrosine-specific); the IEA parent term is correct. Supporting Evidence: PMID:1639064 Here we characterize a human cytosolic 50 kDa protein tyrosine kinase, p50csk, which specifically phosphorylates Tyr-505 of p56lck and a synthetic peptide containing this site |
| GO:0004713 protein tyrosine kinase activity | EXP PMID:1639064 The human p50csk tyrosine kinase phosphorylates p56lck at Ty... | ACCEPT | Summary: CSK is a cytosolic non-receptor protein tyrosine kinase whose principal substrates are the C-terminal regulatory tyrosines of Src-family kinases. This EXP row is supported by direct kinase assays. Reason: Direct biochemical evidence of CSK tyrosine kinase activity on Src-family kinase tails or test substrates. Core activity. Supporting Evidence: PMID:1639064 Here we characterize a human cytosolic 50 kDa protein tyrosine kinase, p50csk, which specifically phosphorylates Tyr-505 of p56lck and a synthetic peptide containing this site |
| GO:0004713 protein tyrosine kinase activity | EXP PMID:7683130 Recombinant Csk expressed in Escherichia coli is autophospho... | ACCEPT | Summary: CSK is a cytosolic non-receptor protein tyrosine kinase whose principal substrates are the C-terminal regulatory tyrosines of Src-family kinases. This EXP row is supported by direct kinase assays. Reason: Direct biochemical evidence of CSK tyrosine kinase activity on Src-family kinase tails or test substrates. Core activity. Supporting Evidence: PMID:7683130 The GST-Csk fusion protein also phosphorylates exogenous substrates, including the heteropolymer poly-Glu/Tyr and enolase |
| GO:0004713 protein tyrosine kinase activity | EXP PMID:9281320 Expression, purification, and initial characterization of hu... | ACCEPT | Summary: CSK is a cytosolic non-receptor protein tyrosine kinase whose principal substrates are the C-terminal regulatory tyrosines of Src-family kinases. This EXP row is supported by direct kinase assays. Reason: Direct biochemical evidence of CSK tyrosine kinase activity on Src-family kinase tails or test substrates. Core activity. Supporting Evidence: PMID:9281320 we show that the enzyme is inactivated by incubation with protein tyrosine kinase Csk in an ATP-Mg-dependent manner, indicating that cellular Yes can be regulated by Csk phosphorylation |
| GO:0004713 protein tyrosine kinase activity | IEA GO_REF:0000120 | ACCEPT | Summary: CSK is a cytosolic non-receptor protein tyrosine kinase whose principal substrates are the C-terminal regulatory tyrosines of Src-family kinases. Reason: Correct electronic mapping (RHEA:10596 / EC 2.7.10.4) consistent with experimental evidence. Supporting Evidence: PMID:1639064 Here we characterize a human cytosolic 50 kDa protein tyrosine kinase, p50csk, which specifically phosphorylates Tyr-505 of p56lck and a synthetic peptide containing this site |
| GO:0004713 protein tyrosine kinase activity | TAS PMID:1945408 cyl encodes a putative cytoplasmic tyrosine kinase lacking t... | ACCEPT | Summary: Traceable author statement from the original cloning paper, which predicted a cytoplasmic tyrosine kinase from sequence. Reason: Activity later confirmed biochemically (PMID:1639064); accept. Supporting Evidence: PMID:1945408 The deduced cyl protein lacks signal and transmembrane sequences but contains features of known cytoplasmic tyrosine kinases, including amino-terminal SH3 and SH2 domains PMID:1639064 Here we characterize a human cytosolic 50 kDa protein tyrosine kinase, p50csk, which specifically phosphorylates Tyr-505 of p56lck and a synthetic peptide containing this site |
| GO:0004713 protein tyrosine kinase activity | TAS Reactome:R-HSA-202233 | ACCEPT | Summary: Reactome reaction in which CSK phosphorylates Lck Tyr-505. Reason: Correct; this is the canonical CSK reaction. Supporting Evidence: Reactome:R-HSA-202233 The inactivating phosphorylation on Y505 is carried out by the Src-specific kinase Csk. |
| GO:0004713 protein tyrosine kinase activity | TAS Reactome:R-HSA-389762 | ACCEPT | Summary: Reactome reaction in which CSK (with Lck) phosphorylates PD-1 ITIM/ITSM tyrosines. Reason: The MF itself is correct for CSK regardless of how important PD-1 is as a substrate; CSK substrate specificity is largely restricted to SFK tails by a docking mechanism (PMID:18614016), so PD-1 is at most a minor substrate. Supporting Evidence: PMID:18614016 it is remarkable that the C-terminal tails of the Src family kinases are the only known targets of Csk |
| GO:0004715 non-membrane spanning protein tyrosine kinase activity | IBA GO_REF:0000033 | ACCEPT | Summary: IBA from PTN001231168 (Bilateria node of PTHR24418, seeded by Drosophila Csk). CSK lacks transmembrane and signal sequences and is a cytosolic tyrosine kinase. Reason: Most precise MF term for CSK and phylogenetically well placed; the activity is in fact older than Bilateria (choanoflagellate Csk orthologs are active tyrosine kinases; PMID:18390552, PMID:16873552). Core function. Supporting Evidence: PMID:1945408 The deduced cyl protein lacks signal and transmembrane sequences but contains features of known cytoplasmic tyrosine kinases, including amino-terminal SH3 and SH2 domains PMID:1639064 Here we characterize a human cytosolic 50 kDa protein tyrosine kinase, p50csk, which specifically phosphorylates Tyr-505 of p56lck and a synthetic peptide containing this site PMID:18390552 MbCsk possessed tyrosine kinase activity, although the specific activity was lower than a comparable preparation of mammalian Csk |
| GO:0005515 protein binding | IPI PMID:10026153 C-terminal Src kinase associates with ligand-stimulated insu... | MODIFY | Summary: CSK SH2 domain binds tyrosine-phosphorylated IGF-1R and insulin receptor after ligand stimulation. Reason: The paper identifies the binding mode (SH2 to phosphotyrosine on the receptor), so a specific MF can replace generic protein binding. Proposed replacements: phosphotyrosine residue binding Supporting Evidence: PMID:10026153 We found that the SH2 domain of CSK binds to the tyrosine-phosphorylated form of IGF-IR and IR |
| GO:0005515 protein binding | IPI PMID:10790433 Phosphoprotein associated with glycosphingolipid-enriched mi... | REMOVE | Summary: PAG (Cbp) binds and recruits CSK to glycosphingolipid-enriched microdomains in resting T cells. Reason: Generic protein binding is uninformative about molecular function. The PAG-CSK interaction is real and functionally important (membrane recruitment of CSK), but the abstract does not itself define the binding mode; the recruitment is captured by plasma membrane / membrane raft localisation and by the phosphotyrosine residue binding term supported elsewhere. REMOVE does not mean the interaction is false; it means GO:0005515 conveys no function. Supporting Evidence: PMID:10790433 Expression of PAG in COS cells results in recruitment of endogenous Csk, altered Src kinase activity, and impaired phosphorylation of Src-specific substrates |
| GO:0005515 protein binding | IPI PMID:12446738 Attenuation of Helicobacter pylori CagA x SHP-2 signaling by... | MODIFY | Summary: CSK SH2 domain binds tyrosine-phosphorylated H. pylori CagA, which stimulates CSK. Reason: Binding mode is defined (SH2 to phospho-CagA); replace with phosphotyrosine residue binding. Host-pathogen context, so non-core in its own right. Proposed replacements: phosphotyrosine residue binding Supporting Evidence: PMID:12446738 Csk selectively binds tyrosine-phosphorylated CagA via its SH2 domain |
| GO:0005515 protein binding | IPI PMID:14665621 Roles of Gab1 and SHP2 in paxillin tyrosine dephosphorylatio... | REMOVE | Summary: Paxillin association with CSK, lost upon SHP2-mediated paxillin dephosphorylation. Reason: Generic protein binding is uninformative about molecular function. REMOVE does not mean the interaction is false; it means GO:0005515 conveys no function. Supporting Evidence: PMID:14665621 caused dissociation of Csk |
| GO:0005515 protein binding | IPI PMID:15683240 Probing the communication between the regulatory and catalyt... | REMOVE | Summary: Biochemistry of CSK regulatory/catalytic domain communication using c-Src as substrate. Reason: Generic protein binding is uninformative about molecular function. The interaction with Src is an enzyme-substrate interaction already represented by the tyrosine kinase activity terms. REMOVE does not mean the interaction is false; it means GO:0005515 conveys no function. Supporting Evidence: PMID:15683240 the SH3 and SH2 domains were crucial in maintaining the full activity of Csk, but were not directly involved in Csk recognition of its physiological substrate, Src |
| GO:0005515 protein binding | IPI PMID:16354697 Focal adhesion kinase is a substrate and downstream effector... | REMOVE | Summary: Paper on FAK dephosphorylation by CagA-SHP2; CSK-CagA binding is background. Reason: Generic protein binding is uninformative about molecular function. Where the binding mode is defined it is captured by the MODIFY on the PMID:12446738 row. REMOVE does not mean the interaction is false; it means GO:0005515 conveys no function. |
| GO:0005515 protein binding | IPI PMID:17911601 Inhibition of T cell activation by cyclic adenosine 5'-monop... | REMOVE | Summary: Ezrin/PKA/EBP50/CSK/PAG multiprotein complex in T-cell lipid rafts. Reason: Generic protein binding is uninformative about molecular function. Complex membership is better captured by membrane raft localisation (proposed NEW) and PKA-catalytic subunit binding. REMOVE does not mean the interaction is false; it means GO:0005515 conveys no function. Supporting Evidence: PMID:17911601 which in turn phosphorylates and activates C-terminal Src kinase (Csk) in T cell lipid rafts |
| GO:0005515 protein binding | IPI PMID:17911601 Inhibition of T cell activation by cyclic adenosine 5'-monop... | REMOVE | Summary: Ezrin/PKA/EBP50/CSK/PAG multiprotein complex in T-cell lipid rafts. Reason: Generic protein binding is uninformative about molecular function. Complex membership is better captured by membrane raft localisation (proposed NEW) and PKA-catalytic subunit binding. REMOVE does not mean the interaction is false; it means GO:0005515 conveys no function. Supporting Evidence: PMID:17911601 which in turn phosphorylates and activates C-terminal Src kinase (Csk) in T cell lipid rafts |
| GO:0005515 protein binding | IPI PMID:18070987 Oncogenic association of the Cbp/PAG adaptor protein with th... | REMOVE | Summary: Lymphoma raft signalosome of Lyn and Cbp/PAG. Reason: Generic protein binding is uninformative about molecular function. The cached abstract in fact states that CSK was not part of the B-NHL signalosome, though the curator may have used full-text data. REMOVE does not mean the interaction is false; it means GO:0005515 conveys no function. Supporting Evidence: PMID:18070987 No Csk appears to be part of this B-NHL signalosome |
| GO:0005515 protein binding | IPI PMID:18614016 Structural basis for the recognition of c-Src by its inactiv... | REMOVE | Summary: Crystal structure of the CSK kinase domain in complex with the c-Src kinase domain. Reason: Generic protein binding is uninformative about molecular function. This is an enzyme-substrate docking interface that explains CSK specificity; it is represented by the kinase activity terms rather than a binding term. REMOVE does not mean the interaction is false; it means GO:0005515 conveys no function. Supporting Evidence: PMID:18614016 Csk cannot phosphorylate substrates that lack this docking mechanism because the conventional substrate binding site used by most tyrosine kinases to recognize substrates is destabilized in Csk by a deletion in the activation loop |
| GO:0005515 protein binding | IPI PMID:19167335 Large-scale structural analysis of the classical human prote... | REMOVE | Summary: Large-scale structural study of the human PTP phosphatome; CSK-CD45 interaction. Reason: Generic protein binding is uninformative about molecular function. REMOVE does not mean the interaction is false; it means GO:0005515 conveys no function. |
| GO:0005515 protein binding | IPI PMID:21930792 SCIMP, a transmembrane adaptor protein involved in major his... | MODIFY | Summary: Phosphorylated SCIMP (Tyr-107) binds the CSK SH2 domain as a negative feedback loop in MHC-II signalling. Reason: Binding requires SCIMP tyrosine phosphorylation and is SH2-mediated (UniProt), so phosphotyrosine residue binding is the informative MF. Proposed replacements: phosphotyrosine residue binding Supporting Evidence: PMID:21930792 When phosphorylated, SCIMP binds to the SLP65 adaptor protein and also to the inhibitory kinase Csk |
| GO:0005515 protein binding | IPI PMID:24902122 The Haemophilus ducreyi LspA1 protein inhibits phagocytosis ... | MODIFY | Summary: CSK binds tyrosine-phosphorylated EPIYG motifs of H. ducreyi LspA1 (YL2), which activates CSK. Reason: Phosphorylated YL2 binds and activates CSK; the paper frames this through SH2-domain regulation of CSK. Replace with phosphotyrosine residue binding. Proposed replacements: phosphotyrosine residue binding Supporting Evidence: PMID:24902122 Csk was identified as the predominant mammalian protein interacting with YL2 PMID:24902122 Phosphorylated YL2 increased Csk catalytic activity PMID:24902122 Instead of being controlled by tyrosine phosphorylation, Csk adopts active and inactive conformations that are in dynamic equilibrium and are regulated by the binding of proteins to the Csk SH2 domain |
| GO:0005515 protein binding | IPI PMID:28514442 Architecture of the human interactome defines protein commun... | REMOVE | Summary: High-throughput interactome detection of CSK-PAG1 interaction. Reason: Generic protein binding is uninformative about molecular function. The CSK-PAG1 interaction is well established, but these screens do not define a function. REMOVE does not mean the interaction is false; it means GO:0005515 conveys no function. |
| GO:0005515 protein binding | IPI PMID:31980649 Extensive rewiring of the EGFR network in colorectal cancer ... | REMOVE | Summary: Proteomic EGFR network study detecting CSK-paxillin association. Reason: Generic protein binding is uninformative about molecular function. REMOVE does not mean the interaction is false; it means GO:0005515 conveys no function. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: Binary Y2H interactome (HuRI) hit with KANK4. Reason: Generic protein binding is uninformative about molecular function. Unvalidated screen hit. REMOVE does not mean the interaction is false; it means GO:0005515 conveys no function. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: Binary Y2H interactome (HuRI) hit with DDIT4L. Reason: Generic protein binding is uninformative about molecular function. Unvalidated screen hit. REMOVE does not mean the interaction is false; it means GO:0005515 conveys no function. |
| GO:0005515 protein binding | IPI PMID:32707033 Kinase Interaction Network Expands Functional and Disease Ro... | REMOVE | Summary: High-throughput interactome detection of CSK-PAG1 interaction. Reason: Generic protein binding is uninformative about molecular function. The CSK-PAG1 interaction is well established, but these screens do not define a function. REMOVE does not mean the interaction is false; it means GO:0005515 conveys no function. |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | REMOVE | Summary: High-throughput interactome detection of CSK-PAG1 interaction. Reason: Generic protein binding is uninformative about molecular function. The CSK-PAG1 interaction is well established, but these screens do not define a function. REMOVE does not mean the interaction is false; it means GO:0005515 conveys no function. |
| GO:0005515 protein binding | IPI PMID:7507203 Tyrosine phosphorylation of CD45 phosphotyrosine phosphatase... | REMOVE | Summary: CSK phosphorylates CD45 on tyrosines, creating an Lck binding site. Reason: Generic protein binding is uninformative about molecular function. The CD45 interaction is enzyme-substrate and is captured by tyrosine kinase activity. REMOVE does not mean the interaction is false; it means GO:0005515 conveys no function. Supporting Evidence: PMID:7507203 Here we report that CD45 was phosphorylated by p50csk on two tyrosine residues |
| GO:0005515 protein binding | TAS PMID:8890164 Association of inhibitory tyrosine protein kinase p50csk wit... | MODIFY | Summary: CSK SH3 domain binds the proline-rich PPPLPERTP motif of the phosphatase PEP (PTPN22). Reason: Binding mode defined: SH3 domain to a proline-rich region of a protein tyrosine phosphatase. Both proline-rich region binding and protein phosphatase binding are more informative. Proposed replacements: proline-rich region binding protein phosphatase binding Supporting Evidence: PMID:8890164 this interaction was mediated by the Csk SH3 domain and by a proline-rich region (PPPLPERTP) in the non-catalytic C-terminal portion of PEP |
| GO:0005524 ATP binding | IEA GO_REF:0000002 | ACCEPT | Summary: ATP binding inferred from the kinase domain. Reason: CSK is an ATP-dependent kinase. Supporting Evidence: PMID:9281320 we show that the enzyme is inactivated by incubation with protein tyrosine kinase Csk in an ATP-Mg-dependent manner, indicating that cellular Yes can be regulated by Csk phosphorylation |
| GO:0005737 cytoplasm | IEA GO_REF:0000120 | ACCEPT | Summary: CSK is mainly cytoplasmic. Reason: Consistent with all evidence; CSK lacks membrane anchors and is described as a cytosolic kinase. Supporting Evidence: PMID:1639064 Here we characterize a human cytosolic 50 kDa protein tyrosine kinase, p50csk, which specifically phosphorylates Tyr-505 of p56lck and a synthetic peptide containing this site |
| GO:0005737 cytoplasm | ISS GO_REF:0000024 | ACCEPT | Summary: CSK is mainly cytoplasmic. Reason: Consistent with all evidence; CSK lacks membrane anchors and is described as a cytosolic kinase. Supporting Evidence: PMID:1639064 Here we characterize a human cytosolic 50 kDa protein tyrosine kinase, p50csk, which specifically phosphorylates Tyr-505 of p56lck and a synthetic peptide containing this site |
| GO:0005737 cytoplasm | ISS GO_REF:0000024 | ACCEPT | Summary: CSK is mainly cytoplasmic. Reason: Consistent with all evidence; CSK lacks membrane anchors and is described as a cytosolic kinase. Supporting Evidence: PMID:1639064 Here we characterize a human cytosolic 50 kDa protein tyrosine kinase, p50csk, which specifically phosphorylates Tyr-505 of p56lck and a synthetic peptide containing this site |
| GO:0005737 cytoplasm | TAS PMID:8890164 Association of inhibitory tyrosine protein kinase p50csk wit... | ACCEPT | Summary: CSK is mainly cytoplasmic. Reason: Consistent with all evidence; CSK lacks membrane anchors and is described as a cytosolic kinase. Supporting Evidence: PMID:1639064 Here we characterize a human cytosolic 50 kDa protein tyrosine kinase, p50csk, which specifically phosphorylates Tyr-505 of p56lck and a synthetic peptide containing this site |
| GO:0005829 cytosol | IDA GO_REF:0000052 | ACCEPT | Summary: Human Protein Atlas immunofluorescence shows cytosolic CSK. Reason: Consistent with the cytosolic nature of CSK. Supporting Evidence: PMID:1639064 Here we characterize a human cytosolic 50 kDa protein tyrosine kinase, p50csk, which specifically phosphorylates Tyr-505 of p56lck and a synthetic peptide containing this site |
| GO:0005829 cytosol | IEA GO_REF:0000117 | ACCEPT | Summary: Reactome/ARBA cytosol placement of CSK. Reason: CSK is a soluble cytosolic kinase recruited transiently to membranes. Supporting Evidence: PMID:1639064 Here we characterize a human cytosolic 50 kDa protein tyrosine kinase, p50csk, which specifically phosphorylates Tyr-505 of p56lck and a synthetic peptide containing this site |
| GO:0005829 cytosol | TAS Reactome:R-HSA-202233 | ACCEPT | Summary: Reactome/ARBA cytosol placement of CSK. Reason: CSK is a soluble cytosolic kinase recruited transiently to membranes. Supporting Evidence: PMID:1639064 Here we characterize a human cytosolic 50 kDa protein tyrosine kinase, p50csk, which specifically phosphorylates Tyr-505 of p56lck and a synthetic peptide containing this site |
| GO:0005829 cytosol | TAS Reactome:R-HSA-203774 | ACCEPT | Summary: Reactome/ARBA cytosol placement of CSK. Reason: CSK is a soluble cytosolic kinase recruited transiently to membranes. Supporting Evidence: PMID:1639064 Here we characterize a human cytosolic 50 kDa protein tyrosine kinase, p50csk, which specifically phosphorylates Tyr-505 of p56lck and a synthetic peptide containing this site |
| GO:0005829 cytosol | TAS Reactome:R-HSA-354077 | ACCEPT | Summary: Reactome/ARBA cytosol placement of CSK. Reason: CSK is a soluble cytosolic kinase recruited transiently to membranes. Supporting Evidence: PMID:1639064 Here we characterize a human cytosolic 50 kDa protein tyrosine kinase, p50csk, which specifically phosphorylates Tyr-505 of p56lck and a synthetic peptide containing this site |
| GO:0005829 cytosol | TAS Reactome:R-HSA-354149 | ACCEPT | Summary: Reactome/ARBA cytosol placement of CSK. Reason: CSK is a soluble cytosolic kinase recruited transiently to membranes. Supporting Evidence: PMID:1639064 Here we characterize a human cytosolic 50 kDa protein tyrosine kinase, p50csk, which specifically phosphorylates Tyr-505 of p56lck and a synthetic peptide containing this site |
| GO:0005829 cytosol | TAS Reactome:R-HSA-377641 | ACCEPT | Summary: Reactome/ARBA cytosol placement of CSK. Reason: CSK is a soluble cytosolic kinase recruited transiently to membranes. Supporting Evidence: PMID:1639064 Here we characterize a human cytosolic 50 kDa protein tyrosine kinase, p50csk, which specifically phosphorylates Tyr-505 of p56lck and a synthetic peptide containing this site |
| GO:0005829 cytosol | TAS Reactome:R-HSA-377644 | ACCEPT | Summary: Reactome/ARBA cytosol placement of CSK. Reason: CSK is a soluble cytosolic kinase recruited transiently to membranes. Supporting Evidence: PMID:1639064 Here we characterize a human cytosolic 50 kDa protein tyrosine kinase, p50csk, which specifically phosphorylates Tyr-505 of p56lck and a synthetic peptide containing this site |
| GO:0005829 cytosol | TAS Reactome:R-HSA-389758 | ACCEPT | Summary: Reactome/ARBA cytosol placement of CSK. Reason: CSK is a soluble cytosolic kinase recruited transiently to membranes. Supporting Evidence: PMID:1639064 Here we characterize a human cytosolic 50 kDa protein tyrosine kinase, p50csk, which specifically phosphorylates Tyr-505 of p56lck and a synthetic peptide containing this site |
| GO:0005829 cytosol | TAS Reactome:R-HSA-389759 | ACCEPT | Summary: Reactome/ARBA cytosol placement of CSK. Reason: CSK is a soluble cytosolic kinase recruited transiently to membranes. Supporting Evidence: PMID:1639064 Here we characterize a human cytosolic 50 kDa protein tyrosine kinase, p50csk, which specifically phosphorylates Tyr-505 of p56lck and a synthetic peptide containing this site |
| GO:0005829 cytosol | TAS Reactome:R-HSA-389762 | ACCEPT | Summary: Reactome/ARBA cytosol placement of CSK. Reason: CSK is a soluble cytosolic kinase recruited transiently to membranes. Supporting Evidence: PMID:1639064 Here we characterize a human cytosolic 50 kDa protein tyrosine kinase, p50csk, which specifically phosphorylates Tyr-505 of p56lck and a synthetic peptide containing this site |
| GO:0005829 cytosol | TAS Reactome:R-HSA-432096 | ACCEPT | Summary: Reactome/ARBA cytosol placement of CSK. Reason: CSK is a soluble cytosolic kinase recruited transiently to membranes. Supporting Evidence: PMID:1639064 Here we characterize a human cytosolic 50 kDa protein tyrosine kinase, p50csk, which specifically phosphorylates Tyr-505 of p56lck and a synthetic peptide containing this site |
| GO:0005829 cytosol | TAS Reactome:R-HSA-443905 | ACCEPT | Summary: Reactome/ARBA cytosol placement of CSK. Reason: CSK is a soluble cytosolic kinase recruited transiently to membranes. Supporting Evidence: PMID:1639064 Here we characterize a human cytosolic 50 kDa protein tyrosine kinase, p50csk, which specifically phosphorylates Tyr-505 of p56lck and a synthetic peptide containing this site |
| GO:0005829 cytosol | TAS Reactome:R-HSA-443910 | ACCEPT | Summary: Reactome/ARBA cytosol placement of CSK. Reason: CSK is a soluble cytosolic kinase recruited transiently to membranes. Supporting Evidence: PMID:1639064 Here we characterize a human cytosolic 50 kDa protein tyrosine kinase, p50csk, which specifically phosphorylates Tyr-505 of p56lck and a synthetic peptide containing this site |
| GO:0005829 cytosol | TAS Reactome:R-HSA-8855375 | ACCEPT | Summary: Reactome/ARBA cytosol placement of CSK. Reason: CSK is a soluble cytosolic kinase recruited transiently to membranes. Supporting Evidence: PMID:1639064 Here we characterize a human cytosolic 50 kDa protein tyrosine kinase, p50csk, which specifically phosphorylates Tyr-505 of p56lck and a synthetic peptide containing this site |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9018758 | ACCEPT | Summary: Reactome/ARBA cytosol placement of CSK. Reason: CSK is a soluble cytosolic kinase recruited transiently to membranes. Supporting Evidence: PMID:1639064 Here we characterize a human cytosolic 50 kDa protein tyrosine kinase, p50csk, which specifically phosphorylates Tyr-505 of p56lck and a synthetic peptide containing this site |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9706298 | ACCEPT | Summary: Reactome/ARBA cytosol placement of CSK. Reason: CSK is a soluble cytosolic kinase recruited transiently to membranes. Supporting Evidence: PMID:1639064 Here we characterize a human cytosolic 50 kDa protein tyrosine kinase, p50csk, which specifically phosphorylates Tyr-505 of p56lck and a synthetic peptide containing this site |
| GO:0005886 plasma membrane | IBA GO_REF:0000033 | ACCEPT | Summary: IBA plasma membrane (is_active_in) from the broad Src/Csk node. Reason: CSK acts on membrane-anchored Src-family kinases after recruitment to the plasma membrane by phosphorylated adaptors; is_active_in is appropriate. Supporting Evidence: PMID:10790433 Expression of PAG in COS cells results in recruitment of endogenous Csk, altered Src kinase activity, and impaired phosphorylation of Src-specific substrates |
| GO:0005886 plasma membrane | IEA GO_REF:0000044 | ACCEPT | Summary: UniProt subcellular location mapping (cell membrane, by similarity to mouse). Reason: Correct, given adaptor-mediated recruitment. Supporting Evidence: PMID:10790433 Expression of PAG in COS cells results in recruitment of endogenous Csk, altered Src kinase activity, and impaired phosphorylation of Src-specific substrates |
| GO:0005886 plasma membrane | IPI PMID:10790433 Phosphoprotein associated with glycosphingolipid-enriched mi... | ACCEPT | Summary: PAG recruits endogenous CSK to membranes. Reason: Direct evidence of membrane recruitment of CSK via PAG. Supporting Evidence: PMID:10790433 Expression of PAG in COS cells results in recruitment of endogenous Csk, altered Src kinase activity, and impaired phosphorylation of Src-specific substrates |
| GO:0005886 plasma membrane | ISS GO_REF:0000024 | ACCEPT | Summary: ISS from mouse Csk. Reason: Consistent with adaptor-mediated recruitment. Supporting Evidence: PMID:10790433 Expression of PAG in COS cells results in recruitment of endogenous Csk, altered Src kinase activity, and impaired phosphorylation of Src-specific substrates |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-177923 | ACCEPT | Summary: Reactome reaction placing CSK with paxillin-SRC at the plasma membrane. Reason: Consistent with membrane recruitment. Supporting Evidence: PMID:14665621 caused dissociation of Csk |
| GO:0005911 cell-cell junction | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: IEA from mouse Csk, cell-cell junction. Reason: CSK regulates Src-family kinases at junctions in animal epithelia, but junctional localisation is context-dependent and not a defining feature. |
| GO:0006468 protein phosphorylation | TAS PMID:1945408 cyl encodes a putative cytoplasmic tyrosine kinase lacking t... | ACCEPT | Summary: TAS from the cloning paper. Reason: CSK phosphorylates proteins; general but correct. More informative terms are present. Supporting Evidence: PMID:1639064 Here we characterize a human cytosolic 50 kDa protein tyrosine kinase, p50csk, which specifically phosphorylates Tyr-505 of p56lck and a synthetic peptide containing this site |
| GO:0008285 negative regulation of cell population proliferation | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: IEA from rat Csk (IDA, adenoviral Csk overexpression in arthritic synovium). Reason: Csk suppresses SFK-driven proliferation and transformation; pleiotropic downstream consequence of SFK inhibition rather than a direct CSK process. |
| GO:0010989 negative regulation of low-density lipoprotein particle clearance | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: IEA from rat Csk (IDA in Csk-transfected J774 macrophages). Reason: Overexpression-based downstream phenotype; no evidence that CSK has a specific role in LDL particle clearance. |
| GO:0019903 protein phosphatase binding | IEA GO_REF:0000107 | ACCEPT | Summary: IEA from rat Csk (IPI with PEP/PTPN22). Reason: The CSK SH3 domain binds the phosphatase PEP/PTPN22; this pairing coordinates SFK inactivation. Supporting Evidence: PMID:8890164 this interaction was mediated by the Csk SH3 domain and by a proline-rich region (PPPLPERTP) in the non-catalytic C-terminal portion of PEP |
| GO:0031295 T cell costimulation | TAS Reactome:R-HSA-388841 | MARK AS OVER ANNOTATED | Summary: Reactome pathway "Regulation of T cell activation by CD28 family" (PD-1 phosphorylation). Reason: CSK is not a component of costimulatory signalling; its role in this Reactome pathway is inhibitory phosphorylation of PD-1/SFKs. The process is better represented by negative regulation of T cell receptor signaling pathway. Supporting Evidence: PMID:8890164 We previously showed that Csk is a potent negative regulator of antigen receptor signaling in T lymphocytes |
| GO:0032715 negative regulation of interleukin-6 production | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: IEA from rat Csk (overexpression in arthritic synovium). Reason: Indirect overexpression phenotype; no specific role in IL-6 production. |
| GO:0034236 protein kinase A catalytic subunit binding | IPI PMID:17911601 Inhibition of T cell activation by cyclic adenosine 5'-monop... | KEEP AS NON CORE | Summary: CSK co-immunoprecipitates with the PKA catalytic subunit in a T-cell raft complex; PKA phosphorylates CSK Ser-364. Reason: Real, specific interaction, but it reflects CSK being a PKA substrate/regulatory target rather than a CSK function. Supporting Evidence: PMID:17911601 which in turn phosphorylates and activates C-terminal Src kinase (Csk) in T cell lipid rafts |
| GO:0034332 adherens junction organization | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: IBA from PTN002815304 (Euteleostomi node), seeded only by rat Csk (RGD:1308800), whose own annotation is IEP (expression in rat seminiferous epithelium). Reason: SFK regulation at adherens junctions is plausible in animal epithelia, but the seed is expression-based and CSK does not organise junctions directly. Animal-specific context; keep as non-core. |
| GO:0034332 adherens junction organization | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: IEA from rat Csk (IEP). Reason: As for the IBA row: plausible animal-specific context, weak evidence. |
| GO:0035556 intracellular signal transduction | IEA GO_REF:0000107 | ACCEPT | Summary: IEA from mouse Csk. Reason: CSK is a signalling kinase acting in intracellular signal transduction; general but correct. Supporting Evidence: PMID:10790433 the PAG-Csk complex transmits negative regulatory signals and thus may help to keep resting T cells in a quiescent state |
| GO:0042802 identical protein binding | IPI PMID:19888460 The tyrosine kinase Csk dimerizes through Its SH3 domain. | KEEP AS NON CORE | Summary: CSK homodimerizes through its SH3 domain. Reason: Biophysically demonstrated, but the physiological role of the dimer is unclear. Supporting Evidence: PMID:19888460 We have discovered that Csk forms homodimers through interactions mediated by the SH3 domain in a manner that buries the recognition surface for SH3 ligands |
| GO:0042997 negative regulation of Golgi to plasma membrane protein transport | IDA PMID:20605918 The Lyn kinase C-lobe mediates Golgi export of Lyn through c... | KEEP AS NON CORE | Summary: CSK-induced closed conformation of Lyn blocks ACSL3-dependent Golgi export of Lyn. Reason: Experimentally supported but specific to Lyn trafficking; a consequence of SFK closure by CSK. Supporting Evidence: PMID:20605918 Formation of a closed conformation by CSK prevents Lyn from associating with ACSL3, resulting in blockade of Lyn export from the Golgi |
| GO:0045779 negative regulation of bone resorption | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: IEA from rat Csk (IDA, adenoviral Csk in osteoclasts). Reason: Csk inhibition of Src in osteoclasts is mechanistically plausible; tissue-specific, animal-specific process. |
| GO:0048709 oligodendrocyte differentiation | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: IEA from rat Csk, whose source annotation is IEP (expression change during oligodendrocyte development). Reason: Expression-pattern evidence does not show participation in oligodendrocyte differentiation. |
| GO:0050765 negative regulation of phagocytosis | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: IEA from rat Csk (IDA, Csk-transfected macrophages). Reason: Supported independently in human cells: CSK activity inhibits SFK-dependent Fc-gamma-R phagocytosis. Supporting Evidence: PMID:24902122 LspA virulence factors of H. ducreyi inhibit phagocytosis by stimulating the catalytic activity of C-terminal Src kinase (Csk), which itself inhibits Src family protein tyrosine kinases (SFKs) that promote phagocytosis |
| GO:0050776 regulation of immune response | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: ARBA machine-learning rule. Reason: CSK is a negative regulator of immune receptor signalling; correct but broad. Supporting Evidence: PMID:8890164 We previously showed that Csk is a potent negative regulator of antigen receptor signaling in T lymphocytes |
| GO:0050852 T cell receptor signaling pathway | TAS Reactome:R-HSA-202403 | MODIFY | Summary: Reactome TCR signaling. Reason: CSK acts as an inhibitor of TCR signalling; the more precise term is negative regulation of T cell receptor signaling pathway. Proposed replacements: negative regulation of T cell receptor signaling pathway Supporting Evidence: PMID:8890164 We previously showed that Csk is a potent negative regulator of antigen receptor signaling in T lymphocytes PMID:1639064 Phosphorylation of Tyr-505 suppressed the catalytic activity of p56lck |
| GO:0050860 negative regulation of T cell receptor signaling pathway | IEA GO_REF:0000107 | ACCEPT | Summary: IEA from mouse Csk (IMP). Reason: Well established: CSK inactivates Lck/Fyn and, with PAG and PEP/PTPN22, restrains TCR signalling. Supporting Evidence: PMID:8890164 We previously showed that Csk is a potent negative regulator of antigen receptor signaling in T lymphocytes PMID:10790433 the PAG-Csk complex transmits negative regulatory signals and thus may help to keep resting T cells in a quiescent state |
| GO:0050868 negative regulation of T cell activation | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: IEA from mouse Csk. Reason: Correct downstream consequence of inhibiting TCR signalling. Supporting Evidence: PMID:10790433 the PAG-Csk complex transmits negative regulatory signals and thus may help to keep resting T cells in a quiescent state |
| GO:0051239 regulation of multicellular organismal process | IEA GO_REF:0000117 | MARK AS OVER ANNOTATED | Summary: ARBA rule, regulation of multicellular organismal process. Reason: Extremely broad, uninformative grouping term. |
| GO:0060368 regulation of Fc receptor mediated stimulatory signaling pathway | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: IBA from PTN002815304, seeded by rat Csk IDA in FcepsilonRI signalling. Reason: CSK regulates SFK-initiated Fc receptor signalling in mast cells/immune cells; animal-specific context. |
| GO:0060368 regulation of Fc receptor mediated stimulatory signaling pathway | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: IEA from rat Csk. Reason: As for the IBA row. |
| GO:0070062 extracellular exosome | HDA PMID:19056867 Large-scale proteomics and phosphoproteomics of urinary exos... | KEEP AS NON CORE | Summary: Urinary exosome proteomics. Reason: Large-scale detection of a cytosolic protein in exosomes; not a functional location. |
| GO:0070064 proline-rich region binding | IEA GO_REF:0000107 | ACCEPT | Summary: IEA from rat Csk (PEP proline-rich region binding by SH3). Reason: Directly supported by the SH3-PEP mapping. Supporting Evidence: PMID:8890164 this interaction was mediated by the Csk SH3 domain and by a proline-rich region (PPPLPERTP) in the non-catalytic C-terminal portion of PEP |
| GO:0070373 negative regulation of ERK1 and ERK2 cascade | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: IEA from rat Csk (FcepsilonRI study). Reason: Downstream consequence of SFK inhibition. |
| GO:0071375 cellular response to peptide hormone stimulus | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: IEA from rat Csk. Reason: Response-to-stimulus annotation without evidence of a specific CSK role in peptide hormone responses beyond SH2 binding to activated IGF-1R/IR. |
| GO:1990782 protein tyrosine kinase binding | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: IEA from rat Csk. Reason: CSK binds its SFK substrates via a docking interface and binds activated receptor tyrosine kinases via its SH2 domain; correct but adds little beyond kinase activity. Supporting Evidence: PMID:18614016 Csk cannot phosphorylate substrates that lack this docking mechanism because the conventional substrate binding site used by most tyrosine kinases to recognize substrates is destabilized in Csk by a deletion in the activation loop |
| GO:0061099 negative regulation of protein tyrosine kinase activity | IDA PMID:1639064 The human p50csk tyrosine kinase phosphorylates p56lck at Ty... | NEW | Summary: CSK directly catalyses the inhibitory phosphorylation of the Src-family kinase C-terminal tail, suppressing their kinase activity. Reason: Participation test: CSK itself performs the regulatory step (phosphorylation of Lck Tyr-505, Yes inactivation). Not redundant with existing process rows, which describe downstream signalling consequences. The term is sparsely used in GO (e.g. SRCIN1, PTK6), so the comparator check gives no convention against it. Supporting Evidence: PMID:1639064 Phosphorylation of Tyr-505 suppressed the catalytic activity of p56lck PMID:9281320 we show that the enzyme is inactivated by incubation with protein tyrosine kinase Csk in an ATP-Mg-dependent manner, indicating that cellular Yes can be regulated by Csk phosphorylation |
| GO:0045121 membrane raft | IDA PMID:17911601 Inhibition of T cell activation by cyclic adenosine 5'-monop... | NEW | Summary: CSK is recruited to lipid rafts by phosphorylated PAG/Cbp and is activated there by PKA. Reason: Raft localisation is where CSK meets its membrane-anchored SFK substrates; supported in T cells. Supporting Evidence: PMID:17911601 which in turn phosphorylates and activates C-terminal Src kinase (Csk) in T cell lipid rafts PMID:10790433 Expression of PAG in COS cells results in recruitment of endogenous Csk, altered Src kinase activity, and impaired phosphorylation of Src-specific substrates |
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Download this section (compressed HTML)Q: Did Csk phosphorylation inhibit Src before animals? Monosiga ovata and M. brevicollis studies (PMID:16873552, PMID:18390552) found weak or no inhibition of choanoflagellate Src, whereas a later yeast/in vitro study (PMID:28939764) reported inhibition for Capsaspora and M. brevicollis proteins. Which assay conditions explain the difference?
Q: Do unicellular holozoans have any functional equivalent of PAG/Cbp or other phosphotyrosine adaptors that recruit Csk to membranes, or is adaptor-based Csk recruitment an animal innovation?
Q: Should the PANTHER IBD of adherens junction organization at PTN002815304, seeded only by an expression-pattern (IEP) annotation of rat Csk, be revisited?
Q: Is SH3-mediated CSK homodimerization (PMID:19888460) physiologically relevant for regulating PTPN22 recruitment in cells?
Experiment: Side-by-side kinetic comparison of human, Monosiga and Capsaspora Csk acting on their cognate and on human Src, using identical purified proteins and both in vitro and SYF-cell assays, to resolve whether tail phosphorylation was inhibitory before animals.
Experiment: Knockout of Csk in Salpingoeca rosetta or Capsaspora owczarzaki, measuring Src activity and colony/aggregate phenotypes, to test whether Csk has a role in premetazoan multicellular stages.
Experiment: Proximity labelling of CSK in human T cells with and without PAG1/SCIMP to map adaptor-dependent CSK localisation and substrates beyond Src-family kinases.
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