LCP2 encodes SLP-76 (SH2 domain-containing leukocyte protein of 76 kDa), a cytosolic adaptor protein of hematopoietic cells with no catalytic activity. It has an N-terminal acidic region with tyrosines (Y113, Y128, Y145) that are phosphorylated by ZAP70 in T cells or SYK in myeloid cells and platelets and then bind the SH2 domains of VAV1, NCK and the Tec kinase ITK; a central proline-rich region whose RxxK motif is bound with high affinity by the C-terminal SH3 domain of GRAP2/GADS, which links SLP-76 to phosphorylated LAT; and a C-terminal SH2 domain that binds phosphorylated ADAP/FYB1, FYB2, CD6 and HPK1. After antigen receptor engagement SLP-76 is recruited from the cytosol into LAT-nucleated signaling microclusters at the immunological synapse, where it assembles the signalosome that activates PLCG1 (via ITK), Ras/ERK, VAV1/NCK-dependent actin polymerization, PKC-theta/NF-kB and ADAP-dependent integrin activation. A proline-rich segment (residues ~185-200) also binds the PLCG1 SH3 domain directly; this conserved interaction within the LAT-GADS-SLP-76-PLCG1 complex is of deliberately low affinity, and raising it increases PLCG1 activity and perturbs thymocyte selection and T cell memory, so it tunes TCR signal strength. HPK1/MAP4K1 phosphorylates SLP-76 on Ser376, which recruits 14-3-3 proteins and provides negative feedback on TCR signaling. SLP-76 has also been reported to bind SUMO-RANGAP1 at the cytoplasmic filaments of the nuclear pore complex (via Lys56) and to promote nuclear import of NFATC1 and NF-kB p65 in activated T cells. It is required for T cell receptor signaling and thymocyte development, and for ITAM-receptor signaling in other cells, including FcERI signaling in mast cells and GPVI/CLEC-2 signaling in platelets. Biallelic loss-of-function variants cause a combined immunodeficiency with neutrophil and platelet defects.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0002376 immune system process | IEA GO_REF:0000117 | MODIFY | Summary: ARBA machine-learning IEA to the root-level term immune system process. Reason: Correct but too general. LCP2 is an adaptor in antigen-receptor signaling; the specific, well-supported process is T cell receptor signaling pathway (plus FcERI signaling in mast cells). Proposed replacements: T cell receptor signaling pathway Supporting Evidence: PMID:9665884 coupling of TCR-regulated PTKs to downstream signaling pathways requires SLP-76 |
| GO:0005515 protein binding | IPI PMID:10229072 Association of Nck with tyrosine-phosphorylated SLP-76 in ac... | MODIFY | Summary: IPI protein binding between LCP2 (SLP-76) and NCK1 (PMID:10229072). Reason: Generic protein binding is uninformative. The cited study shows that tyrosine-phosphorylated SLP-76 (pY113/pY128) is bound by the NCK SH2 domain, i.e. SLP-76 provides phosphotyrosine docking motifs for SH2 domains; SH2 domain binding captures this. Proposed replacements: SH2 domain binding Supporting Evidence: PMID:10229072 In vitro experiments show that the interaction between Nck and SLP-76 is mediated via the Nck SH2 domain PMID:10229072 Y113 and Y128 phosphopeptides could compete binding of SLP-76 to the SH2 domain of Nck |
| GO:0005515 protein binding | IPI PMID:10347175 SLP-76 and Vav function in separate, but overlapping pathway... | MODIFY | Summary: IPI protein binding between LCP2 (SLP-76) and VAV1 (PMID:10347175). Reason: Generic protein binding is uninformative. VAV1 binds ZAP70-phosphorylated N-terminal tyrosines of SLP-76 (Y113/Y128) through the VAV1 SH2 domain; SLP-76 therefore binds an SH2 domain. SH2 domain binding captures the mechanism. Proposed replacements: SH2 domain binding Supporting Evidence: PMID:10347175 associate with each other via the SH2 domain of Vav and phosphorylated tyrosines of SLP-76 PMID:10347175 two tyrosines, Tyr-113 and Tyr-128, of SLP-76 are required for its binding to Vav |
| GO:0005515 protein binding | IPI PMID:10570256 Cutting edge: SLP-76 cooperativity with FYB/FYN-T in the Up-... | MODIFY | Summary: IPI protein binding between LCP2 (SLP-76) and FYB1 (ADAP/SLAP-130) (PMID:10570256). Reason: Generic protein binding is uninformative. The C-terminal SH2 domain of SLP-76 binds phosphorylated tyrosines of FYB1/ADAP (Y595/Y651 in human FYB, Y559 in SLAP-130 numbering). Phosphotyrosine residue binding is the informative MF performed by SLP-76 in this interaction. Proposed replacements: phosphotyrosine residue binding Supporting Evidence: PMID:10570256 FYB is selectively phosphorylated by FYN-T, providing a template for the recruitment of FYN-T and SLP-76 SH2 domains |
| GO:0005515 protein binding | IPI PMID:10671560 Functional association between SLAP-130 and SLP-76 in Jurkat... | MODIFY | Summary: IPI protein binding between LCP2 (SLP-76) and FYB1 (ADAP/SLAP-130) (PMID:10671560). Reason: Generic protein binding is uninformative. The C-terminal SH2 domain of SLP-76 binds phosphorylated tyrosines of FYB1/ADAP (Y595/Y651 in human FYB, Y559 in SLAP-130 numbering). Phosphotyrosine residue binding is the informative MF performed by SLP-76 in this interaction. Proposed replacements: phosphotyrosine residue binding Supporting Evidence: PMID:10671560 we identified tyrosine 559 as critical for the interaction between SLP-76 and SLAP-130 |
| GO:0005515 protein binding | IPI PMID:15929943 Novel Src homology 3 domain-binding motifs identified from p... | MODIFY | Summary: IPI protein binding between LCP2 (SLP-76) and GRAP2 (GADS) (PMID:15929943). Reason: Generic protein binding is uninformative. The proline-rich region of SLP-76 carries an RxxK motif (233-PSIDRSTKP-241) bound with nanomolar affinity by the C-terminal SH3 domain of GADS; this links SLP-76 to phospho-LAT and is essential for efficient TCR signaling. SH3 domain binding captures the SLP-76 side of this interaction. Proposed replacements: SH3 domain binding Supporting Evidence: PMID:15929943 arrays of peptides derived from the proline-rich region of the SH2 domain-containing leukocyte protein of 76 kDa (SLP-76) |
| GO:0005515 protein binding | IPI PMID:15929943 Novel Src homology 3 domain-binding motifs identified from p... | MODIFY | Summary: IPI protein binding between LCP2 (SLP-76) and NCK1 (PMID:15929943). Reason: Generic protein binding is uninformative. The study used peptide arrays from the SLP-76 proline-rich region to map binding sites for SH3 domains, including that of NCK1; SH3 domain binding captures the SLP-76 activity. Proposed replacements: SH3 domain binding Supporting Evidence: PMID:15929943 the PLC-gamma1 SH3 domain was found to associate with SLP-76 through at least three distinct sites |
| GO:0005515 protein binding | IPI PMID:15929943 Novel Src homology 3 domain-binding motifs identified from p... | MODIFY | Summary: IPI protein binding between LCP2 (SLP-76) and PLCG1 (PMID:15929943). Reason: Generic protein binding is uninformative. The study used peptide arrays from the SLP-76 proline-rich region to map binding sites for SH3 domains, including that of PLCG1; SH3 domain binding captures the SLP-76 activity. Proposed replacements: SH3 domain binding Supporting Evidence: PMID:15929943 the PLC-gamma1 SH3 domain was found to associate with SLP-76 through at least three distinct sites |
| GO:0005515 protein binding | IPI PMID:15929943 Novel Src homology 3 domain-binding motifs identified from p... | MODIFY | Summary: IPI protein binding between LCP2 (SLP-76) and GRB2 (PMID:15929943). Reason: Generic protein binding is uninformative. The study used peptide arrays from the SLP-76 proline-rich region to map binding sites for SH3 domains, including that of GRB2; SH3 domain binding captures the SLP-76 activity. Proposed replacements: SH3 domain binding Supporting Evidence: PMID:15929943 the PLC-gamma1 SH3 domain was found to associate with SLP-76 through at least three distinct sites |
| GO:0005515 protein binding | IPI PMID:16189514 Towards a proteome-scale map of the human protein-protein in... | REMOVE | Summary: IPI protein binding between LCP2 (SLP-76) and GRAP2 (GADS) from a proteome-scale yeast two-hybrid screen. Reason: Generic protein binding is uninformative about LCP2 function. This row derives from a high-throughput binary/proteomic screen that reports the interaction without mechanistic or functional data from which a more specific molecular function could be inferred. The GRAP2 (GADS) interaction itself is well established and physiologically important (captured with informative MF terms from focused studies elsewhere in this review), so removal does not dispute the interaction. |
| GO:0005515 protein binding | IPI PMID:16467851 Recruitment and activation of PLCgamma1 in T cells: a new in... | MODIFY | Summary: IPI protein binding between LCP2 (SLP-76) and bovine PLCG1 (PMID:16467851). Reason: Generic protein binding is uninformative. SLP-76 participates, with VAV1 and c-Cbl, in stabilizing PLCG1 recruitment to the LAT-nucleated complex; this is the signaling adaptor activity of SLP-76. Proposed replacements: signaling adaptor activity Supporting Evidence: PMID:16467851 with the participation of Vav1, c-Cbl and Slp76, are required to stabilize PLCgamma1 recruitment |
| GO:0005515 protein binding | IPI PMID:16511262 Expression, refolding and crystallizations of the Grb2-like ... | MODIFY | Summary: IPI protein binding between LCP2 (SLP-76) and mouse Grap2 (Gads) (PMID:16511262). Reason: Generic protein binding is uninformative. The proline-rich region of SLP-76 carries an RxxK motif (233-PSIDRSTKP-241) bound with nanomolar affinity by the C-terminal SH3 domain of GADS; this links SLP-76 to phospho-LAT and is essential for efficient TCR signaling. SH3 domain binding captures the SLP-76 side of this interaction. Proposed replacements: SH3 domain binding Supporting Evidence: PMID:16511262 GADS interacts through its C-terminal SH3 domain with the adaptor protein SLP-76 |
| GO:0005515 protein binding | IPI PMID:17010654 Crystal structure of the C-terminal SH3 domain of the adapto... | MODIFY | Summary: IPI protein binding between LCP2 (SLP-76) and GRAP2 (GADS) (PMID:17010654). Reason: Generic protein binding is uninformative. The proline-rich region of SLP-76 carries an RxxK motif (233-PSIDRSTKP-241) bound with nanomolar affinity by the C-terminal SH3 domain of GADS; this links SLP-76 to phospho-LAT and is essential for efficient TCR signaling. SH3 domain binding captures the SLP-76 side of this interaction. Proposed replacements: SH3 domain binding Supporting Evidence: PMID:17010654 the C-terminal SH3 domain of GADS bound to the SLP-76 motif 233-PSIDRSTKP-241, which represents the minimal binding site |
| GO:0005515 protein binding | IPI PMID:17010654 Crystal structure of the C-terminal SH3 domain of the adapto... | MODIFY | Summary: IPI protein binding between LCP2 (SLP-76) and mouse Grap2 (Gads) (PMID:17010654). Reason: Generic protein binding is uninformative. The proline-rich region of SLP-76 carries an RxxK motif (233-PSIDRSTKP-241) bound with nanomolar affinity by the C-terminal SH3 domain of GADS; this links SLP-76 to phospho-LAT and is essential for efficient TCR signaling. SH3 domain binding captures the SLP-76 side of this interaction. Proposed replacements: SH3 domain binding Supporting Evidence: PMID:17010654 the C-terminal SH3 domain of GADS bound to the SLP-76 motif 233-PSIDRSTKP-241, which represents the minimal binding site |
| GO:0005515 protein binding | IPI PMID:17235283 Efficient T-cell receptor signaling requires a high-affinity... | MODIFY | Summary: IPI protein binding between LCP2 (SLP-76) and GRAP2 (GADS) (PMID:17235283). Reason: Generic protein binding is uninformative. The proline-rich region of SLP-76 carries an RxxK motif (233-PSIDRSTKP-241) bound with nanomolar affinity by the C-terminal SH3 domain of GADS; this links SLP-76 to phospho-LAT and is essential for efficient TCR signaling. SH3 domain binding captures the SLP-76 side of this interaction. Proposed replacements: SH3 domain binding Supporting Evidence: PMID:17235283 the Gads C-terminal SH3 domain binds a core RxxK sequence motif in the SLP-76 scaffold |
| GO:0005515 protein binding | IPI PMID:17235283 Efficient T-cell receptor signaling requires a high-affinity... | REMOVE | Summary: IPI protein binding between LCP2 (SLP-76) and STAM2 (PMID:17235283). Reason: Generic protein binding is uninformative, and the STAM2 SH3 domain binding was an in vitro SH3-array cross-reactivity of an SLP-76 RxxK peptide that the authors themselves state has no physiological correlate. Supporting Evidence: PMID:17235283 SLP-76 has not been physiologically linked to the STAM proteins in vivo |
| GO:0005515 protein binding | IPI PMID:17235283 Efficient T-cell receptor signaling requires a high-affinity... | MODIFY | Summary: IPI protein binding between LCP2 (SLP-76) and GRB2 (PMID:17235283). Reason: Generic protein binding is uninformative. The SLP-76 RxxK peptide bound the GRB2 C-terminal SH3 domain on SH3 arrays (a weaker cross-reactivity than GADS C-SH3). SH3 domain binding is the informative MF. Proposed replacements: SH3 domain binding Supporting Evidence: PMID:17235283 the SLP-76 peptide only bound detectably to the Gads C-, Grb2 C-, STAM1 and STAM2 SH3 domains |
| GO:0005515 protein binding | IPI PMID:17235283 Efficient T-cell receptor signaling requires a high-affinity... | REMOVE | Summary: IPI protein binding between LCP2 (SLP-76) and STAM (PMID:17235283). Reason: Generic protein binding is uninformative, and the STAM SH3 domain binding was an in vitro SH3-array cross-reactivity of an SLP-76 RxxK peptide that the authors themselves state has no physiological correlate. Supporting Evidence: PMID:17235283 SLP-76 has not been physiologically linked to the STAM proteins in vivo |
| GO:0005515 protein binding | IPI PMID:17420479 SLP-76 mediates and maintains activation of the Tec family k... | MODIFY | Summary: IPI protein binding between LCP2 (SLP-76) and ITK (PMID:17420479). Reason: Generic protein binding is uninformative. SLP-76 nucleates a TCR-induced complex with ITK and is required for ITK activation and for ITK-mediated PLCG1 phosphorylation; this is signaling adaptor activity (possibly also a kinase activator activity, see suggested questions). Proposed replacements: signaling adaptor activity Supporting Evidence: PMID:17420479 We propose that SLP-76 is required for ITK activation; furthermore, an ongoing physical interaction between SLP-76 and ITK is required to maintain ITK in an active conformation |
| GO:0005515 protein binding | IPI PMID:19380743 Charting the molecular network of the drug target Bcr-Abl. | REMOVE | Summary: IPI protein binding between LCP2 (SLP-76) and GRB2 from a tandem-affinity purification/mass spectrometry map of the Bcr-Abl network in K562 leukemia cells. Reason: Generic protein binding is uninformative about LCP2 function. This row derives from a high-throughput binary/proteomic screen that reports the interaction without mechanistic or functional data from which a more specific molecular function could be inferred. The GRB2 interaction itself is well established and physiologically important (captured with informative MF terms from focused studies elsewhere in this review), so removal does not dispute the interaction. |
| GO:0005515 protein binding | IPI PMID:19523899 Distinct binding modes of two epitopes in Gab2 that interact... | MODIFY | Summary: IPI protein binding between LCP2 (SLP-76) and mouse Grap2 (Gads) (PMID:19523899). Reason: Generic protein binding is uninformative. The proline-rich region of SLP-76 carries an RxxK motif (233-PSIDRSTKP-241) bound with nanomolar affinity by the C-terminal SH3 domain of GADS; this links SLP-76 to phospho-LAT and is essential for efficient TCR signaling. SH3 domain binding captures the SLP-76 side of this interaction. The cached abstract does not describe this interaction in detail; support is from focused structural/biophysical studies of the GADS C-SH3/SLP-76 RxxK interaction. Proposed replacements: SH3 domain binding Supporting Evidence: PMID:17235283 the Gads C-terminal SH3 domain binds a core RxxK sequence motif in the SLP-76 scaffold |
| GO:0005515 protein binding | IPI PMID:20534575 SH2 domain containing leukocyte phosphoprotein of 76-kDa (SL... | MODIFY | Summary: IPI protein binding between LCP2 (SLP-76) and FYB1 (ADAP/SLAP-130) (PMID:20534575). Reason: Generic protein binding is uninformative. The C-terminal SH2 domain of SLP-76 binds phosphorylated tyrosines of FYB1/ADAP (Y595/Y651 in human FYB, Y559 in SLAP-130 numbering). Phosphotyrosine residue binding is the informative MF performed by SLP-76 in this interaction. The cached record for this paper does not describe the FYB1 interaction mechanism (abstract only or not mentioned), so support is taken from focused studies of the SLP-76 SH2-ADAP interaction. Proposed replacements: phosphotyrosine residue binding Supporting Evidence: PMID:22074159 phosphorylated Tyr 595 of ADAP may serve as a direct binding site for the SH2 domains of the T cell proteins SLP76 and NCK |
| GO:0005515 protein binding | IPI PMID:20534575 SH2 domain containing leukocyte phosphoprotein of 76-kDa (SL... | MODIFY | Summary: IPI protein binding between LCP2 (SLP-76) and GRAP2 (GADS) (PMID:20534575). Reason: Generic protein binding is uninformative. The proline-rich region of SLP-76 carries an RxxK motif (233-PSIDRSTKP-241) bound with nanomolar affinity by the C-terminal SH3 domain of GADS; this links SLP-76 to phospho-LAT and is essential for efficient TCR signaling. SH3 domain binding captures the SLP-76 side of this interaction. The cached abstract does not describe this interaction in detail; support is from focused structural/biophysical studies of the GADS C-SH3/SLP-76 RxxK interaction. Proposed replacements: SH3 domain binding Supporting Evidence: PMID:17235283 the Gads C-terminal SH3 domain binds a core RxxK sequence motif in the SLP-76 scaffold |
| GO:0005515 protein binding | IPI PMID:20562827 Cooperative interactions at the SLP-76 complex are critical ... | MODIFY | Summary: IPI protein binding between LCP2 (SLP-76) and NCK1 (PMID:20562827). Reason: Generic protein binding is uninformative. SLP-76 nucleates a complex with NCK and VAV1 that regulates TCR-induced actin polymerization; signaling adaptor activity captures SLP-76 role. Proposed replacements: signaling adaptor activity Supporting Evidence: PMID:20562827 Generation of a complex of SLP-76, Nck and VAV1 is crucial for regulation of the actin machinery |
| GO:0005515 protein binding | IPI PMID:20936779 A human MAP kinase interactome. | REMOVE | Summary: IPI protein binding between LCP2 (SLP-76) and GRB2 from a yeast two-hybrid human MAP kinase interactome screen. Reason: Generic protein binding is uninformative about LCP2 function. This row derives from a high-throughput binary/proteomic screen that reports the interaction without mechanistic or functional data from which a more specific molecular function could be inferred. The GRB2 interaction itself is well established and physiologically important (captured with informative MF terms from focused studies elsewhere in this review), so removal does not dispute the interaction. |
| GO:0005515 protein binding | IPI PMID:21516116 Next-generation sequencing to generate interactome datasets. | REMOVE | Summary: IPI protein binding between LCP2 (SLP-76) and GRAP2 (GADS) from a next-generation-sequencing-based yeast two-hybrid interactome screen. Reason: Generic protein binding is uninformative about LCP2 function. This row derives from a high-throughput binary/proteomic screen that reports the interaction without mechanistic or functional data from which a more specific molecular function could be inferred. The GRAP2 (GADS) interaction itself is well established and physiologically important (captured with informative MF terms from focused studies elsewhere in this review), so removal does not dispute the interaction. |
| GO:0005515 protein binding | IPI PMID:21725281 Sequential phosphorylation of SLP-76 at tyrosine 173 is requ... | MODIFY | Summary: IPI protein binding between LCP2 (SLP-76) and VAV1 (PMID:21725281). Reason: Generic protein binding is uninformative. Phosphorylated tyrosines of SLP-76 recruit VAV1 into the SLP-76/GADS/LAT signaling complex in T and mast cells; this is signaling adaptor activity. Proposed replacements: signaling adaptor activity Supporting Evidence: PMID:21725281 In T and mast cells, antigen receptor signalling is nucleated by three adaptors: SLP-76, Gads and LAT PMID:21725281 Three well-characterized SLP-76 tyrosine phosphorylation sites recruit key components, including a Tec-family tyrosine kinase, Itk |
| GO:0005515 protein binding | IPI PMID:21725281 Sequential phosphorylation of SLP-76 at tyrosine 173 is requ... | MODIFY | Summary: IPI protein binding between LCP2 (SLP-76) and NCK1 (PMID:21725281). Reason: Generic protein binding is uninformative. Phosphorylated tyrosines of SLP-76 recruit NCK1 into the SLP-76/GADS/LAT signaling complex in T and mast cells; this is signaling adaptor activity. Proposed replacements: signaling adaptor activity Supporting Evidence: PMID:21725281 In T and mast cells, antigen receptor signalling is nucleated by three adaptors: SLP-76, Gads and LAT PMID:21725281 Three well-characterized SLP-76 tyrosine phosphorylation sites recruit key components, including a Tec-family tyrosine kinase, Itk |
| GO:0005515 protein binding | IPI PMID:21725281 Sequential phosphorylation of SLP-76 at tyrosine 173 is requ... | MODIFY | Summary: IPI protein binding between LCP2 (SLP-76) and PLCG1 (PMID:21725281). Reason: Generic protein binding is uninformative. Phosphorylated tyrosines of SLP-76 recruit PLCG1 into the SLP-76/GADS/LAT signaling complex in T and mast cells; this is signaling adaptor activity. Proposed replacements: signaling adaptor activity Supporting Evidence: PMID:21725281 In T and mast cells, antigen receptor signalling is nucleated by three adaptors: SLP-76, Gads and LAT PMID:21725281 Three well-characterized SLP-76 tyrosine phosphorylation sites recruit key components, including a Tec-family tyrosine kinase, Itk |
| GO:0005515 protein binding | IPI PMID:21725281 Sequential phosphorylation of SLP-76 at tyrosine 173 is requ... | MODIFY | Summary: IPI protein binding between LCP2 (SLP-76) and ITK (PMID:21725281). Reason: Generic protein binding is uninformative. Phosphorylated tyrosines of SLP-76 recruit ITK into the SLP-76/GADS/LAT signaling complex in T and mast cells; this is signaling adaptor activity. Proposed replacements: signaling adaptor activity Supporting Evidence: PMID:21725281 In T and mast cells, antigen receptor signalling is nucleated by three adaptors: SLP-76, Gads and LAT PMID:21725281 Three well-characterized SLP-76 tyrosine phosphorylation sites recruit key components, including a Tec-family tyrosine kinase, Itk |
| GO:0005515 protein binding | IPI PMID:21983831 The kinase GLK controls autoimmunity and NF-ΞΊB signaling by ... | MODIFY | Summary: IPI protein binding between LCP2 (SLP-76) and MAP4K3 (GLK) (PMID:21983831). Reason: Generic protein binding is uninformative. TCR signaling induces a direct interaction of GLK (MAP4K3) with SLP-76 that activates GLK upstream of PKC-theta; SLP-76 acts as the upstream signaling adaptor. Proposed replacements: signaling adaptor activity Supporting Evidence: PMID:21983831 TCR signaling activated GLK by inducing its direct interaction with the upstream adaptor SLP-76 |
| GO:0005515 protein binding | IPI PMID:21983831 The kinase GLK controls autoimmunity and NF-ΞΊB signaling by ... | MODIFY | Summary: IPI protein binding between LCP2 (SLP-76) and mouse Map4k3 (GLK) (PMID:21983831). Reason: Generic protein binding is uninformative. TCR signaling induces a direct interaction of GLK (MAP4K3) with SLP-76 that activates GLK upstream of PKC-theta; SLP-76 acts as the upstream signaling adaptor. Proposed replacements: signaling adaptor activity Supporting Evidence: PMID:21983831 TCR signaling activated GLK by inducing its direct interaction with the upstream adaptor SLP-76 |
| GO:0005515 protein binding | IPI PMID:22074159 Improved two-dimensional reversed phase-reversed phase LC-MS... | MODIFY | Summary: IPI protein binding between LCP2 (SLP-76) and FYB1 (ADAP/SLAP-130) (PMID:22074159). Reason: Generic protein binding is uninformative. The C-terminal SH2 domain of SLP-76 binds phosphorylated tyrosines of FYB1/ADAP (Y595/Y651 in human FYB, Y559 in SLAP-130 numbering). Phosphotyrosine residue binding is the informative MF performed by SLP-76 in this interaction. Proposed replacements: phosphotyrosine residue binding Supporting Evidence: PMID:22074159 phosphorylated Tyr 595 of ADAP may serve as a direct binding site for the SH2 domains of the T cell proteins SLP76 and NCK |
| GO:0005515 protein binding | IPI PMID:24584089 Quantitative proteomics analysis of signalosome dynamics in ... | MODIFY | Summary: IPI protein binding between LCP2 (SLP-76) and CD6 (PMID:24584089). Reason: Generic protein binding is uninformative. In primary T cells CD6 recruits SLP-76; UniProt records that the SLP-76 SH2 domain binds the tyrosine-phosphorylated CD6 C-terminus. Phosphotyrosine residue binding is the informative MF. Proposed replacements: phosphotyrosine residue binding Supporting Evidence: PMID:24584089 The surface receptor CD6 was able to initiate its own signaling pathway by recruiting SLP-76 and the guanine nucleotide-exchange factor Vav1 regardless of the presence of Lat |
| GO:0005515 protein binding | IPI PMID:24658140 The mammalian-membrane two-hybrid assay (MaMTH) for probing ... | REMOVE | Summary: IPI protein binding between LCP2 (SLP-76) and EGFR from a mammalian-membrane two-hybrid (MaMTH) assay development screen. Reason: Generic protein binding is uninformative about LCP2 function. This row derives from a high-throughput binary/proteomic screen that reports the interaction without mechanistic or functional data from which a more specific molecular function could be inferred. EGFR is not a known physiological partner of SLP-76 in antigen-receptor signaling; the interaction has no functional follow-up. |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | REMOVE | Summary: IPI protein binding between LCP2 (SLP-76) and NCK2 from the HI-II-14 proteome-scale yeast two-hybrid map. Reason: Generic protein binding is uninformative about LCP2 function. This row derives from a high-throughput binary/proteomic screen that reports the interaction without mechanistic or functional data from which a more specific molecular function could be inferred. The NCK2 interaction itself is well established and physiologically important (captured with informative MF terms from focused studies elsewhere in this review), so removal does not dispute the interaction. |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | REMOVE | Summary: IPI protein binding between LCP2 (SLP-76) and GRAP2 (GADS) from the HI-II-14 proteome-scale yeast two-hybrid map. Reason: Generic protein binding is uninformative about LCP2 function. This row derives from a high-throughput binary/proteomic screen that reports the interaction without mechanistic or functional data from which a more specific molecular function could be inferred. The GRAP2 (GADS) interaction itself is well established and physiologically important (captured with informative MF terms from focused studies elsewhere in this review), so removal does not dispute the interaction. |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | REMOVE | Summary: IPI protein binding between LCP2 (SLP-76) and STAM2 from the HI-II-14 proteome-scale yeast two-hybrid map. Reason: Generic protein binding is uninformative about LCP2 function. This row derives from a high-throughput binary/proteomic screen that reports the interaction without mechanistic or functional data from which a more specific molecular function could be inferred. STAM2 is not a known physiological partner of SLP-76 in antigen-receptor signaling; the interaction has no functional follow-up. |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | REMOVE | Summary: IPI protein binding between LCP2 (SLP-76) and FXR2 from the HI-II-14 proteome-scale yeast two-hybrid map. Reason: Generic protein binding is uninformative about LCP2 function. This row derives from a high-throughput binary/proteomic screen that reports the interaction without mechanistic or functional data from which a more specific molecular function could be inferred. FXR2 is not a known physiological partner of SLP-76 in antigen-receptor signaling; the interaction has no functional follow-up. |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | REMOVE | Summary: IPI protein binding between LCP2 (SLP-76) and GRB2 from the HI-II-14 proteome-scale yeast two-hybrid map. Reason: Generic protein binding is uninformative about LCP2 function. This row derives from a high-throughput binary/proteomic screen that reports the interaction without mechanistic or functional data from which a more specific molecular function could be inferred. The GRB2 interaction itself is well established and physiologically important (captured with informative MF terms from focused studies elsewhere in this review), so removal does not dispute the interaction. |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | REMOVE | Summary: IPI protein binding between LCP2 (SLP-76) and GOLGA2 from the HI-II-14 proteome-scale yeast two-hybrid map. Reason: Generic protein binding is uninformative about LCP2 function. This row derives from a high-throughput binary/proteomic screen that reports the interaction without mechanistic or functional data from which a more specific molecular function could be inferred. GOLGA2 is not a known physiological partner of SLP-76 in antigen-receptor signaling; the interaction has no functional follow-up. |
| GO:0005515 protein binding | IPI PMID:25814554 Phospho-tyrosine dependent protein-protein interaction netwo... | MODIFY | Summary: IPI protein binding between LCP2 (SLP-76) and FYB1 (ADAP/SLAP-130) (PMID:25814554). Reason: Generic protein binding is uninformative. The C-terminal SH2 domain of SLP-76 binds phosphorylated tyrosines of FYB1/ADAP (Y595/Y651 in human FYB, Y559 in SLAP-130 numbering). Phosphotyrosine residue binding is the informative MF performed by SLP-76 in this interaction. The cached record for this paper does not describe the FYB1 interaction mechanism (abstract only or not mentioned), so support is taken from focused studies of the SLP-76 SH2-ADAP interaction. Proposed replacements: phosphotyrosine residue binding Supporting Evidence: PMID:22074159 phosphorylated Tyr 595 of ADAP may serve as a direct binding site for the SH2 domains of the T cell proteins SLP76 and NCK |
| GO:0005515 protein binding | IPI PMID:26871637 Widespread Expansion of Protein Interaction Capabilities by ... | REMOVE | Summary: IPI protein binding between LCP2 (SLP-76) and NCK2 from a proteome-scale two-hybrid screen of alternatively spliced isoforms. Reason: Generic protein binding is uninformative about LCP2 function. This row derives from a high-throughput binary/proteomic screen that reports the interaction without mechanistic or functional data from which a more specific molecular function could be inferred. The NCK2 interaction itself is well established and physiologically important (captured with informative MF terms from focused studies elsewhere in this review), so removal does not dispute the interaction. |
| GO:0005515 protein binding | IPI PMID:27107012 Pooled-matrix protein interaction screens using Barcode Fusi... | REMOVE | Summary: IPI protein binding between LCP2 (SLP-76) and GRAP2 (GADS) from a pooled Barcode Fusion Genetics yeast two-hybrid screen. Reason: Generic protein binding is uninformative about LCP2 function. This row derives from a high-throughput binary/proteomic screen that reports the interaction without mechanistic or functional data from which a more specific molecular function could be inferred. The GRAP2 (GADS) interaction itself is well established and physiologically important (captured with informative MF terms from focused studies elsewhere in this review), so removal does not dispute the interaction. |
| GO:0005515 protein binding | IPI PMID:27335501 ARAP, a Novel Adaptor Protein, Is Required for TCR Signaling... | MODIFY | Summary: IPI protein binding between LCP2 (SLP-76) and FYB1 (ADAP/SLAP-130) (PMID:27335501). Reason: Generic protein binding is uninformative. The SLP-76 SH2 domain binds the phosphorylated YDDV motifs of ARAP/FYB2 (and of its paralog ADAP/FYB1) after TCR stimulation; phosphotyrosine residue binding captures this. Proposed replacements: phosphotyrosine residue binding Supporting Evidence: PMID:27335501 ARAP associated with the Src homology 2 domain of Src homology 2-containing leukocyte protein of 76 kDa via the phosphorylation of two YDDV motifs in response to TCR stimulation |
| GO:0005515 protein binding | IPI PMID:27335501 ARAP, a Novel Adaptor Protein, Is Required for TCR Signaling... | MODIFY | Summary: IPI protein binding between LCP2 (SLP-76) and FYB2 (ARAP) (PMID:27335501). Reason: Generic protein binding is uninformative. The SLP-76 SH2 domain binds the phosphorylated YDDV motifs of ARAP/FYB2 (and of its paralog ADAP/FYB1) after TCR stimulation; phosphotyrosine residue binding captures this. Proposed replacements: phosphotyrosine residue binding Supporting Evidence: PMID:27335501 ARAP associated with the Src homology 2 domain of Src homology 2-containing leukocyte protein of 76 kDa via the phosphorylation of two YDDV motifs in response to TCR stimulation |
| GO:0005515 protein binding | IPI PMID:29997244 LuTHy: a double-readout bioluminescence-based two-hybrid tec... | REMOVE | Summary: IPI protein binding between LCP2 (SLP-76) and GRAP2 (GADS) from the LuTHy bioluminescence two-hybrid technology benchmark. Reason: Generic protein binding is uninformative about LCP2 function. This row derives from a high-throughput binary/proteomic screen that reports the interaction without mechanistic or functional data from which a more specific molecular function could be inferred. The GRAP2 (GADS) interaction itself is well established and physiologically important (captured with informative MF terms from focused studies elsewhere in this review), so removal does not dispute the interaction. |
| GO:0005515 protein binding | IPI PMID:31467278 Maximizing binary interactome mapping with a minimal number ... | REMOVE | Summary: IPI protein binding between LCP2 (SLP-76) and GRAP2 (GADS) from a multi-assay binary interactome mapping study. Reason: Generic protein binding is uninformative about LCP2 function. This row derives from a high-throughput binary/proteomic screen that reports the interaction without mechanistic or functional data from which a more specific molecular function could be inferred. The GRAP2 (GADS) interaction itself is well established and physiologically important (captured with informative MF terms from focused studies elsewhere in this review), so removal does not dispute the interaction. |
| GO:0005515 protein binding | IPI PMID:31467278 Maximizing binary interactome mapping with a minimal number ... | REMOVE | Summary: IPI protein binding between LCP2 (SLP-76) and NCK1 from a multi-assay binary interactome mapping study. Reason: Generic protein binding is uninformative about LCP2 function. This row derives from a high-throughput binary/proteomic screen that reports the interaction without mechanistic or functional data from which a more specific molecular function could be inferred. The NCK1 interaction itself is well established and physiologically important (captured with informative MF terms from focused studies elsewhere in this review), so removal does not dispute the interaction. |
| GO:0005515 protein binding | IPI PMID:31515488 Extensive disruption of protein interactions by genetic vari... | REMOVE | Summary: IPI protein binding between LCP2 (SLP-76) and FXR2 from a large-scale screen of variant effects on binary interactions. Reason: Generic protein binding is uninformative about LCP2 function. This row derives from a high-throughput binary/proteomic screen that reports the interaction without mechanistic or functional data from which a more specific molecular function could be inferred. FXR2 is not a known physiological partner of SLP-76 in antigen-receptor signaling; the interaction has no functional follow-up. |
| GO:0005515 protein binding | IPI PMID:31980649 Extensive rewiring of the EGFR network in colorectal cancer ... | REMOVE | Summary: IPI protein binding between LCP2 (SLP-76) and EGFR from an AP-MS study of the EGFR network in colorectal cancer cells. Reason: Generic protein binding is uninformative about LCP2 function. This row derives from a high-throughput binary/proteomic screen that reports the interaction without mechanistic or functional data from which a more specific molecular function could be inferred. EGFR is not a known physiological partner of SLP-76 in antigen-receptor signaling; the interaction has no functional follow-up. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: IPI protein binding between LCP2 (SLP-76) and NCK2 from the HuRI reference binary interactome (yeast two-hybrid). Reason: Generic protein binding is uninformative about LCP2 function. This row derives from a high-throughput binary/proteomic screen that reports the interaction without mechanistic or functional data from which a more specific molecular function could be inferred. The NCK2 interaction itself is well established and physiologically important (captured with informative MF terms from focused studies elsewhere in this review), so removal does not dispute the interaction. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: IPI protein binding between LCP2 (SLP-76) and GRAP2 (GADS) from the HuRI reference binary interactome (yeast two-hybrid). Reason: Generic protein binding is uninformative about LCP2 function. This row derives from a high-throughput binary/proteomic screen that reports the interaction without mechanistic or functional data from which a more specific molecular function could be inferred. The GRAP2 (GADS) interaction itself is well established and physiologically important (captured with informative MF terms from focused studies elsewhere in this review), so removal does not dispute the interaction. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: IPI protein binding between LCP2 (SLP-76) and STAM2 from the HuRI reference binary interactome (yeast two-hybrid). Reason: Generic protein binding is uninformative about LCP2 function. This row derives from a high-throughput binary/proteomic screen that reports the interaction without mechanistic or functional data from which a more specific molecular function could be inferred. STAM2 is not a known physiological partner of SLP-76 in antigen-receptor signaling; the interaction has no functional follow-up. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: IPI protein binding between LCP2 (SLP-76) and FXR2 from the HuRI reference binary interactome (yeast two-hybrid). Reason: Generic protein binding is uninformative about LCP2 function. This row derives from a high-throughput binary/proteomic screen that reports the interaction without mechanistic or functional data from which a more specific molecular function could be inferred. FXR2 is not a known physiological partner of SLP-76 in antigen-receptor signaling; the interaction has no functional follow-up. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: IPI protein binding between LCP2 (SLP-76) and GRB2 from the HuRI reference binary interactome (yeast two-hybrid). Reason: Generic protein binding is uninformative about LCP2 function. This row derives from a high-throughput binary/proteomic screen that reports the interaction without mechanistic or functional data from which a more specific molecular function could be inferred. The GRB2 interaction itself is well established and physiologically important (captured with informative MF terms from focused studies elsewhere in this review), so removal does not dispute the interaction. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: IPI protein binding between LCP2 (SLP-76) and GOLGA2 from the HuRI reference binary interactome (yeast two-hybrid). Reason: Generic protein binding is uninformative about LCP2 function. This row derives from a high-throughput binary/proteomic screen that reports the interaction without mechanistic or functional data from which a more specific molecular function could be inferred. GOLGA2 is not a known physiological partner of SLP-76 in antigen-receptor signaling; the interaction has no functional follow-up. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: IPI protein binding between LCP2 (SLP-76) and LNX1 from the HuRI reference binary interactome (yeast two-hybrid). Reason: Generic protein binding is uninformative about LCP2 function. This row derives from a high-throughput binary/proteomic screen that reports the interaction without mechanistic or functional data from which a more specific molecular function could be inferred. LNX1 is not a known physiological partner of SLP-76 in antigen-receptor signaling; the interaction has no functional follow-up. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: IPI protein binding between LCP2 (SLP-76) and ELOVL6 from the HuRI reference binary interactome (yeast two-hybrid). Reason: Generic protein binding is uninformative about LCP2 function. This row derives from a high-throughput binary/proteomic screen that reports the interaction without mechanistic or functional data from which a more specific molecular function could be inferred. ELOVL6 is not a known physiological partner of SLP-76 in antigen-receptor signaling; the interaction has no functional follow-up. |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | REMOVE | Summary: IPI protein binding between LCP2 (SLP-76) and GRAP2 (GADS) from a yeast two-hybrid neurodegenerative-disease interactome. Reason: Generic protein binding is uninformative about LCP2 function. This row derives from a high-throughput binary/proteomic screen that reports the interaction without mechanistic or functional data from which a more specific molecular function could be inferred. The GRAP2 (GADS) interaction itself is well established and physiologically important (captured with informative MF terms from focused studies elsewhere in this review), so removal does not dispute the interaction. |
| GO:0005515 protein binding | IPI PMID:37398436 AI-guided pipeline for protein-protein interaction drug disc... | REMOVE | Summary: IPI protein binding between LCP2 (SLP-76) and GRAP2 (GADS) from a high-throughput PPI screen from an AI-guided drug-discovery pipeline. Reason: Generic protein binding is uninformative about LCP2 function. This row derives from a high-throughput binary/proteomic screen that reports the interaction without mechanistic or functional data from which a more specific molecular function could be inferred. The GRAP2 (GADS) interaction itself is well established and physiologically important (captured with informative MF terms from focused studies elsewhere in this review), so removal does not dispute the interaction. |
| GO:0005515 protein binding | IPI PMID:8673706 Vav and SLP-76 interact and functionally cooperate in IL-2 g... | MODIFY | Summary: IPI protein binding between LCP2 (SLP-76) and VAV1 (PMID:8673706). Reason: Generic protein binding is uninformative. VAV1 binds ZAP70-phosphorylated N-terminal tyrosines of SLP-76 (Y113/Y128) through the VAV1 SH2 domain; SLP-76 therefore binds an SH2 domain. SH2 domain binding captures the mechanism. Proposed replacements: SH2 domain binding Supporting Evidence: PMID:8673706 The Vav SH2 domain is required for this interaction |
| GO:0005515 protein binding | IPI PMID:9047237 Regulation of Vav-SLP-76 binding by ZAP-70 and its relevance... | MODIFY | Summary: IPI protein binding between LCP2 (SLP-76) and VAV1 (PMID:9047237). Reason: Generic protein binding is uninformative. VAV1 binds ZAP70-phosphorylated N-terminal tyrosines of SLP-76 (Y113/Y128) through the VAV1 SH2 domain; SLP-76 therefore binds an SH2 domain. SH2 domain binding captures the mechanism. Proposed replacements: SH2 domain binding Supporting Evidence: PMID:9047237 only ZAP-70 phosphorylates SLP-76 at specific sites that allow Vav SH2 domain binding |
| GO:0005737 cytoplasm | IBA GO_REF:0000033 | ACCEPT | Summary: IBA: cytoplasm (is_active_in) from the SLP-76/BLNK/CLNK family node. Reason: SLP-76 is a cytosolic adaptor that is recruited to membrane signaling microclusters on receptor engagement; cytoplasm is correct at this level of generality. Supporting Evidence: PMID:20551903 which is rapidly recruited from the cytosol to microclusters |
| GO:0005737 cytoplasm | IEA GO_REF:0000044 | ACCEPT | Summary: IEA from UniProt subcellular location (Cytoplasm). Reason: Consistent with the cytosolic localization of SLP-76. |
| GO:0005829 cytosol | IDA GO_REF:0000052 | ACCEPT | Summary: IDA cytosol from Human Protein Atlas immunofluorescence. Reason: SLP-76 resides in the cytosol of resting cells before recruitment to LAT/GADS microclusters. |
| GO:0005829 cytosol | IDA PMID:20551903 Ezrin tunes T-cell activation by controlling Dlg1 and microt... | ACCEPT | Summary: IDA cytosol, PMID:20551903 (Ezrin/immunological synapse study in Jurkat cells). Reason: The paper describes SLP-76 as recruited from the cytosol to TCR microclusters. Supporting Evidence: PMID:20551903 SLP-76 is a central scaffold molecule of the TCR signalling cascade |
| GO:0005829 cytosol | TAS Reactome:R-HSA-202216 | ACCEPT | Summary: Reactome TAS cytosol (Reactome:R-HSA-202216), a reaction in TCR, FcERI or GPVI signaling in which SLP-76 is a participant. Reason: SLP-76 is a cytosolic adaptor and Reactome places its signaling reactions in the cytosol; location is correct. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-202241 | ACCEPT | Summary: Reactome TAS cytosol (Reactome:R-HSA-202241), a reaction in TCR, FcERI or GPVI signaling in which SLP-76 is a participant. Reason: SLP-76 is a cytosolic adaptor and Reactome places its signaling reactions in the cytosol; location is correct. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-202248 | ACCEPT | Summary: Reactome TAS cytosol (Reactome:R-HSA-202248), a reaction in TCR, FcERI or GPVI signaling in which SLP-76 is a participant. Reason: SLP-76 is a cytosolic adaptor and Reactome places its signaling reactions in the cytosol; location is correct. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-202331 | ACCEPT | Summary: Reactome TAS cytosol (Reactome:R-HSA-202331), a reaction in TCR, FcERI or GPVI signaling in which SLP-76 is a participant. Reason: SLP-76 is a cytosolic adaptor and Reactome places its signaling reactions in the cytosol; location is correct. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-202375 | ACCEPT | Summary: Reactome TAS cytosol (Reactome:R-HSA-202375), a reaction in TCR, FcERI or GPVI signaling in which SLP-76 is a participant. Reason: SLP-76 is a cytosolic adaptor and Reactome places its signaling reactions in the cytosol; location is correct. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-213407 | ACCEPT | Summary: Reactome TAS cytosol (Reactome:R-HSA-213407), a reaction in TCR, FcERI or GPVI signaling in which SLP-76 is a participant. Reason: SLP-76 is a cytosolic adaptor and Reactome places its signaling reactions in the cytosol; location is correct. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-2396561 | ACCEPT | Summary: Reactome TAS cytosol (Reactome:R-HSA-2396561), a reaction in TCR, FcERI or GPVI signaling in which SLP-76 is a participant. Reason: SLP-76 is a cytosolic adaptor and Reactome places its signaling reactions in the cytosol; location is correct. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-2396594 | ACCEPT | Summary: Reactome TAS cytosol (Reactome:R-HSA-2396594), a reaction in TCR, FcERI or GPVI signaling in which SLP-76 is a participant. Reason: SLP-76 is a cytosolic adaptor and Reactome places its signaling reactions in the cytosol; location is correct. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-2396606 | ACCEPT | Summary: Reactome TAS cytosol (Reactome:R-HSA-2396606), a reaction in TCR, FcERI or GPVI signaling in which SLP-76 is a participant. Reason: SLP-76 is a cytosolic adaptor and Reactome places its signaling reactions in the cytosol; location is correct. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-2424476 | ACCEPT | Summary: Reactome TAS cytosol (Reactome:R-HSA-2424476), a reaction in TCR, FcERI or GPVI signaling in which SLP-76 is a participant. Reason: SLP-76 is a cytosolic adaptor and Reactome places its signaling reactions in the cytosol; location is correct. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-2424481 | ACCEPT | Summary: Reactome TAS cytosol (Reactome:R-HSA-2424481), a reaction in TCR, FcERI or GPVI signaling in which SLP-76 is a participant. Reason: SLP-76 is a cytosolic adaptor and Reactome places its signaling reactions in the cytosol; location is correct. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-2424484 | ACCEPT | Summary: Reactome TAS cytosol (Reactome:R-HSA-2424484), a reaction in TCR, FcERI or GPVI signaling in which SLP-76 is a participant. Reason: SLP-76 is a cytosolic adaptor and Reactome places its signaling reactions in the cytosol; location is correct. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-2424485 | ACCEPT | Summary: Reactome TAS cytosol (Reactome:R-HSA-2424485), a reaction in TCR, FcERI or GPVI signaling in which SLP-76 is a participant. Reason: SLP-76 is a cytosolic adaptor and Reactome places its signaling reactions in the cytosol; location is correct. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-2424486 | ACCEPT | Summary: Reactome TAS cytosol (Reactome:R-HSA-2424486), a reaction in TCR, FcERI or GPVI signaling in which SLP-76 is a participant. Reason: SLP-76 is a cytosolic adaptor and Reactome places its signaling reactions in the cytosol; location is correct. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-2424487 | ACCEPT | Summary: Reactome TAS cytosol (Reactome:R-HSA-2424487), a reaction in TCR, FcERI or GPVI signaling in which SLP-76 is a participant. Reason: SLP-76 is a cytosolic adaptor and Reactome places its signaling reactions in the cytosol; location is correct. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-2730833 | ACCEPT | Summary: Reactome TAS cytosol (Reactome:R-HSA-2730833), a reaction in TCR, FcERI or GPVI signaling in which SLP-76 is a participant. Reason: SLP-76 is a cytosolic adaptor and Reactome places its signaling reactions in the cytosol; location is correct. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-2730840 | ACCEPT | Summary: Reactome TAS cytosol (Reactome:R-HSA-2730840), a reaction in TCR, FcERI or GPVI signaling in which SLP-76 is a participant. Reason: SLP-76 is a cytosolic adaptor and Reactome places its signaling reactions in the cytosol; location is correct. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-2730841 | ACCEPT | Summary: Reactome TAS cytosol (Reactome:R-HSA-2730841), a reaction in TCR, FcERI or GPVI signaling in which SLP-76 is a participant. Reason: SLP-76 is a cytosolic adaptor and Reactome places its signaling reactions in the cytosol; location is correct. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-2730847 | ACCEPT | Summary: Reactome TAS cytosol (Reactome:R-HSA-2730847), a reaction in TCR, FcERI or GPVI signaling in which SLP-76 is a participant. Reason: SLP-76 is a cytosolic adaptor and Reactome places its signaling reactions in the cytosol; location is correct. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-2730851 | ACCEPT | Summary: Reactome TAS cytosol (Reactome:R-HSA-2730851), a reaction in TCR, FcERI or GPVI signaling in which SLP-76 is a participant. Reason: SLP-76 is a cytosolic adaptor and Reactome places its signaling reactions in the cytosol; location is correct. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-2730856 | ACCEPT | Summary: Reactome TAS cytosol (Reactome:R-HSA-2730856), a reaction in TCR, FcERI or GPVI signaling in which SLP-76 is a participant. Reason: SLP-76 is a cytosolic adaptor and Reactome places its signaling reactions in the cytosol; location is correct. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-2730858 | ACCEPT | Summary: Reactome TAS cytosol (Reactome:R-HSA-2730858), a reaction in TCR, FcERI or GPVI signaling in which SLP-76 is a participant. Reason: SLP-76 is a cytosolic adaptor and Reactome places its signaling reactions in the cytosol; location is correct. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-2730889 | ACCEPT | Summary: Reactome TAS cytosol (Reactome:R-HSA-2730889), a reaction in TCR, FcERI or GPVI signaling in which SLP-76 is a participant. Reason: SLP-76 is a cytosolic adaptor and Reactome places its signaling reactions in the cytosol; location is correct. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-2730892 | ACCEPT | Summary: Reactome TAS cytosol (Reactome:R-HSA-2730892), a reaction in TCR, FcERI or GPVI signaling in which SLP-76 is a participant. Reason: SLP-76 is a cytosolic adaptor and Reactome places its signaling reactions in the cytosol; location is correct. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-429449 | ACCEPT | Summary: Reactome TAS cytosol (Reactome:R-HSA-429449), a reaction in TCR, FcERI or GPVI signaling in which SLP-76 is a participant. Reason: SLP-76 is a cytosolic adaptor and Reactome places its signaling reactions in the cytosol; location is correct. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-430135 | ACCEPT | Summary: Reactome TAS cytosol (Reactome:R-HSA-430135), a reaction in TCR, FcERI or GPVI signaling in which SLP-76 is a participant. Reason: SLP-76 is a cytosolic adaptor and Reactome places its signaling reactions in the cytosol; location is correct. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-430158 | ACCEPT | Summary: Reactome TAS cytosol (Reactome:R-HSA-430158), a reaction in TCR, FcERI or GPVI signaling in which SLP-76 is a participant. Reason: SLP-76 is a cytosolic adaptor and Reactome places its signaling reactions in the cytosol; location is correct. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-430180 | ACCEPT | Summary: Reactome TAS cytosol (Reactome:R-HSA-430180), a reaction in TCR, FcERI or GPVI signaling in which SLP-76 is a participant. Reason: SLP-76 is a cytosolic adaptor and Reactome places its signaling reactions in the cytosol; location is correct. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-430183 | ACCEPT | Summary: Reactome TAS cytosol (Reactome:R-HSA-430183), a reaction in TCR, FcERI or GPVI signaling in which SLP-76 is a participant. Reason: SLP-76 is a cytosolic adaptor and Reactome places its signaling reactions in the cytosol; location is correct. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-430190 | ACCEPT | Summary: Reactome TAS cytosol (Reactome:R-HSA-430190), a reaction in TCR, FcERI or GPVI signaling in which SLP-76 is a participant. Reason: SLP-76 is a cytosolic adaptor and Reactome places its signaling reactions in the cytosol; location is correct. |
| GO:0005911 cell-cell junction | IEA GO_REF:0000107 | MODIFY | Summary: IEA (Ensembl Compara) cell-cell junction transferred from mouse Lcp2. Reason: The relevant cell contact for SLP-76 is the immunological synapse, where SLP-76 microclusters form and move after TCR engagement. In GO, immunological synapse is not a descendant of cell-cell junction, so the more accurate location term is proposed. Proposed replacements: immunological synapse Supporting Evidence: PMID:20551903 rapidly recruited from the cytosol to microclusters that then move from the periphery to the centre of the immunological synapse |
| GO:0006955 immune response | TAS PMID:7706237 Molecular cloning of SLP-76, a 76-kDa tyrosine phosphoprotei... | MODIFY | Summary: TAS immune response from the SLP-76 cloning paper. Reason: Correct but too general. The cloning paper places SLP-76 in TCR intracellular signal transduction; the specific process is T cell receptor signaling pathway. Proposed replacements: T cell receptor signaling pathway Supporting Evidence: PMID:7706237 is likely to play an important role in TCR-mediated intracellular signal transduction |
| GO:0007169 cell surface receptor protein tyrosine kinase signaling pathway | IBA GO_REF:0000033 | MODIFY | Summary: IBA to cell surface receptor protein tyrosine kinase signaling pathway, from PANTHER node PTN001019935 (SLP-76/BLNK/CLNK family). Reason: GO defines this term as signaling from receptors that themselves possess tyrosine kinase activity. SLP-76 acts downstream of non-catalytic immunoreceptors (TCR, FcERI, GPVI/FcR-gamma) that recruit cytoplasmic Src/Syk-family kinases (ZAP70, SYK), and GO does not place T cell receptor signaling pathway under this term. The IBA reflects the family broad role as a tyrosine-kinase substrate adaptor, but it misstates the receptor class for LCP2. Replace with T cell receptor signaling pathway; the receptor-specific terms (T cell receptor signaling pathway, Fc-epsilon receptor signaling pathway) are the accurate annotations. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH ROLE CONFLATION Sources checked: PANTHER:PTN001019935 SUPPORTS SOURCE BUT NOT TARGET SLP-76/BLNK/CLNK family node; the adaptor role downstream of tyrosine kinases is inherited, but for LCP2 the kinases are cytoplasmic (ZAP70/SYK) acting on non-catalytic immunoreceptors, not receptor tyrosine kinases. MGI:MGI:1351468 UNRESOLVED Mouse descendant evidence listed in WITH/FROM; not inspected in detail here. Proposed replacements: T cell receptor signaling pathway Supporting Evidence: PMID:9665884 coupling of TCR-regulated PTKs to downstream signaling pathways requires SLP-76 |
| GO:0007169 cell surface receptor protein tyrosine kinase signaling pathway | TAS PMID:7706237 Molecular cloning of SLP-76, a 76-kDa tyrosine phosphoprotei... | MODIFY | Summary: TAS to cell surface receptor protein tyrosine kinase signaling pathway from the SLP-76 cloning paper. Reason: The cloning paper describes SLP-76 as a substrate of the TCR-activated tyrosine kinase pathway; the TCR has no intrinsic kinase activity, so the receptor tyrosine kinase pathway term is inaccurate. Replace with T cell receptor signaling pathway. Proposed replacements: T cell receptor signaling pathway Supporting Evidence: PMID:7706237 One substrate of the TCR-activated protein tyrosine kinase pathway is a 76-kDa protein (pp76) PMID:7706237 is likely to play an important role in TCR-mediated intracellular signal transduction |
| GO:0030674 protein-macromolecule adaptor activity | IBA GO_REF:0000033 | ACCEPT | Summary: IBA protein-macromolecule adaptor activity (PANTHER PTN001019935). Reason: SLP-76 has no catalytic domain; it is a phosphorylation-dependent adaptor whose N-terminal pY motifs, central proline-rich GADS-binding region and C-terminal SH2 domain assemble VAV1, NCK, ITK, PLCG1, GADS/LAT and ADAP into a signaling complex. This is the core MF (the more specific child signaling adaptor activity is used in core_functions). Supporting Evidence: PMID:7706237 Although no recognizable motifs related to tyrosine, serine/threonine, or lipid kinase domains are present in the predicted amino acid sequence, it contains several potential motifs recognized by SH2 and SH3 domains PMID:21725281 In T and mast cells, antigen receptor signalling is nucleated by three adaptors: SLP-76, Gads and LAT |
| GO:0035556 intracellular signal transduction | IBA GO_REF:0000033 | ACCEPT | Summary: IBA intracellular signal transduction. Reason: Correct general parent of the antigen-receptor signaling cascades in which SLP-76 acts as an adaptor. Supporting Evidence: PMID:7706237 is likely to play an important role in TCR-mediated intracellular signal transduction |
| GO:0036398 TCR signalosome | IBA GO_REF:0000033 | ACCEPT | Summary: IBA part_of TCR signalosome. Reason: SLP-76 is a core component of the LAT/GADS/SLP-76 signalosome assembled after TCR engagement. Supporting Evidence: PMID:20551903 signalling effectors, such as SLP-76, LAT and ZAP-70 |
| GO:0036398 TCR signalosome | IDA PMID:20551903 Ezrin tunes T-cell activation by controlling Dlg1 and microt... | ACCEPT | Summary: IDA part_of TCR signalosome (PMID:20551903), from imaging of SLP-76 microclusters with phospho-LAT at the immunological synapse. Reason: Direct imaging evidence of SLP-76 in pLAT-containing TCR signaling microclusters. Supporting Evidence: PMID:20551903 SLP-76 microcluster aggregates were also enriched in pLAT |
| GO:0044853 plasma membrane raft | IDA PMID:20551903 Ezrin tunes T-cell activation by controlling Dlg1 and microt... | UNDECIDED | Summary: IDA plasma membrane raft (PMID:20551903). Reason: The cached full text of PMID:20551903 describes SLP-76 in TCR microclusters at the immunological synapse but contains no statement about membrane rafts or raft fractionation, so the evidence cannot be verified here. SLP-76 is cytosolic and is recruited to membrane via GADS/phospho-LAT, so raft association is plausible but indirect; left undecided rather than overruling the curator. |
| GO:0045576 mast cell activation | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: IBA mast cell activation (PANTHER node PTN002679793). Reason: SLP-76 performs adaptor work in FcERI signaling in mast cells (SLP-76-deficient mast cells fail to degranulate or secrete IL-6), so it participates in the signaling that activates mast cells. The more precise description of its role is Fc-epsilon receptor signaling pathway (proposed as NEW); mast cell activation is kept as a valid but non-core cellular outcome. Supporting Evidence: PMID:10377180 These results suggest that SLP-76 plays an important role in FcepsilonRI-mediated signaling in mast cells PMID:21725281 degranulation and IL-6 production in mast cells |
| GO:0045860 positive regulation of protein kinase activity | IEP PMID:14624253 T cell receptor-independent basal signaling via Erk and Abl ... | MARK AS OVER ANNOTATED | Summary: IEP positive regulation of protein kinase activity (PMID:14624253, basal Erk/Abl signaling and RAG expression in Jurkat signaling mutants). Reason: IEP (expression pattern) evidence does not show that SLP-76 regulates kinase activity; in this paper SLP-76 appears mainly as a mutant background (J14) and through its mRNA level. SLP-76 is required for ITK activation (PMID:17420479), so a kinase-regulatory role is biologically plausible, but that is a consequence of its adaptor activity and the cited evidence does not support this annotation. Supporting Evidence: PMID:14624253 These results point to a requirement for the LAT/SLP-76 module to transmit a signal(s) initiated by engagement of the TCR to the downstream calcium and MAPK pathways |
| GO:0050852 T cell receptor signaling pathway | IDA PMID:20551903 Ezrin tunes T-cell activation by controlling Dlg1 and microt... | ACCEPT | Summary: IDA T cell receptor signaling pathway (PMID:20551903). Reason: Core process. SLP-76 couples TCR-activated ZAP70 to PLCG1, Ras/ERK, VAV1/NCK-actin and NF-kB outputs; SLP-76-deficient Jurkat cells are uncoupled from PLCG1 activation and TCR-induced gene expression. Supporting Evidence: PMID:20551903 SLP-76 is a central scaffold molecule of the TCR signalling cascade PMID:9665884 was required for optimal tyrosine phosphorylation and activation of phospholipase C-gamma1 (PLC-gamma1), as well as Ras pathway activation |
| GO:0038095 Fc-epsilon receptor signaling pathway | IMP PMID:10377180 SLP-76 deficiency impairs signaling via the high-affinity Ig... | NEW | Summary: Proposed NEW: SLP-76 acts as an adaptor in FcERI signaling in mast cells. Reason: Participation test: SLP-76 does part of the work of the pathway as the adaptor that couples FcERI-activated SYK to PLCG1 phosphorylation and calcium mobilization (the same adaptor role it has in TCR signaling). Comparator check: the partner adaptors of the same complex (LAT, GRAP2/GADS) and SYK are standard members of this pathway. Evidence: SLP-76-deficient mast cells lack FcERI-induced PLCG1 phosphorylation, calcium flux, degranulation and IL-6 secretion, and the SLP-76 Y173 site is needed for FcERI-induced PLCG1 phosphorylation in mast cells. Supporting Evidence: PMID:10377180 Tyrosine phosphorylation of phospholipase C-gamma1 (but not of Syk) and calcium mobilization in response to IgE cross-linking were reduced in SLP-76-deficient BMMCs PMID:21725281 Y173 was required for antigen receptor-induced phosphorylation of phospholipase C- |
| GO:0038065 collagen-activated signaling pathway | TAS PMID:18826392 Differential roles for the adapters Gads and LAT in platelet... | NEW | Summary: Proposed NEW: SLP-76 is an adaptor in platelet GPVI/FcR-gamma (collagen receptor) signaling. Reason: Participation test: in platelets SLP-76 performs the same adaptor work as in T cells, linking SYK-phosphorylated signaling to PLCG2 activation downstream of the collagen receptor GPVI/FcR-gamma. Comparator: its partner adaptors LAT and GADS are analysed in the same pathway (PMID:18826392). Human SLP-76 deficiency impairs platelet aggregation. Kept as a non-core, cell-type-specific use of the core adaptor activity. Supporting Evidence: PMID:18826392 The adapter proteins SLP-76 and LAT have been shown to play critical roles in the activation of PLCgamma2 in platelets downstream of GPVI/FcRgamma and the C-type lectin receptor CLEC-2 PMID:33231617 severe neutrophil defects, and impaired platelet aggregation file:human/LCP2/LCP2-deep-research-falcon.md SLP-76 participates in ITAM-receptor signaling downstream of the collagen receptor GPVI, contributing to integrin activation, cytoskeletal reorganization, and platelet activation |
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Download this section (compressed HTML)Q: Beyond scaffolding, does SLP-76 act as a direct activator of ITK (holding it in the active conformation, PMID:17420479), and would this justify a protein kinase activator activity MF in addition to signaling adaptor activity?
Q: Should the SLP-76/BLNK/CLNK PANTHER node carry cell surface receptor protein tyrosine kinase signaling pathway, given that the receptors these adaptors serve (TCR, BCR, FcERI, GPVI) lack intrinsic kinase activity?
Q: Is there direct evidence (e.g. detergent-resistant membrane fractionation) that SLP-76 localizes to plasma membrane rafts, supporting the IDA from PMID:20551903?
Q: SLP-76 has been reported to bind SUMO-RANGAP1 at nuclear pore cytoplasmic filaments via Lys56 and to promote NFATC1 and p65 nuclear import (PMID:26321253). Is this independently reproduced, and does it justify a nuclear pore cytoplasmic filament location or a regulation of protein import into nucleus process annotation, given that GOA currently has neither?
Q: SLP-76 binds the PLCG1 SH3 domain directly through PRR185-200 but with deliberately low affinity (PMID:42660881). Does the SH3 domain binding MF fully capture this, or should SLP-76 be modelled as contributing to PLCG1 activation (e.g. a GO-CAM causal edge) within the LAT-GADS-SLP-76-PLCG1 tetramer?
Experiment: Reconstitute SLP-76-deficient human neutrophils or iPSC-derived neutrophils with domain mutants (N-terminal 3YF, GADS-binding RxxK mutant, SH2 R448L) and measure integrin/Fc-gamma receptor-induced PLCG2 activation, ROS and adhesion.
Hypothesis: The neutrophil defect of human SLP-76 deficiency reflects loss of the same N-terminal/GADS/SH2 adaptor modules used in TCR signaling.
Type: genetic complementation with domain mutants
Experiment: Introduce the RANGAP1-binding-deficient K56E substitution into endogenous LCP2 in primary human T cells (base editing) and measure NPC-associated RANGAP1, NFATC1 and p65 nuclear import, and proximal signaling, after TCR stimulation.
Hypothesis: SLP-76 binding to SUMO-RANGAP1 is required for efficient nuclear entry of NFAT and NF-kB in human T cells independently of its proximal adaptor function.
Type: genome editing with functional readouts
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