LAT (linker for activation of T cells) is a small, palmitoylated single-pass (type III) transmembrane adaptor protein of T cells, NK cells, mast cells and platelets with no catalytic activity. Palmitoylation of Cys26/Cys29 targets it to cholesterol-rich plasma membrane microdomains. Following TCR engagement, ZAP70 (and in other cells SYK) phosphorylates multiple cytoplasmic tyrosines (conventionally numbered Y132, Y171, Y191 and Y226 after the originally cloned 233-residue short isoform; Y161, Y200, Y220 and Y255 in the 262-residue canonical long isoform), creating SH2 docking sites for PLCG1 (Y132), GRB2/SOS1, GRAP2 (GADS)-SLP-76 (LCP2), the PI3K p85 subunit and VAV1. Multivalent phospho-LAT and its partners assemble into the TCR signalosome, forming liquid-like membrane condensates that concentrate kinases, exclude phosphatases and couple TCR triggering to calcium mobilization, Ras-MAPK activation, NFAT/AP-1 activation and actin reorganization. Besides the plasma membrane pool, much of LAT resides on intracellular vesicles; surface LAT is phosphorylated first in microclusters, while vesicular LAT, cycled by Rab6/syntaxin-16-dependent retrograde transport to the Golgi/TGN and VAMP7/GMAP210-dependent anterograde delivery, is recruited later to the immunological synapse. LAT plays the same scaffold role downstream of FcepsilonRI in mast cells and the collagen receptor GPVI (and FcgammaRIIA) in platelets. LAT is essential for thymocyte development beyond the DN stage in mice, and loss-of-function mutations in humans cause combined immunodeficiency with autoimmunity (IMD52).
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0001772 immunological synapse | IBA GO_REF:0000033 | ACCEPT | Summary: LAT is recruited into TCR microclusters at the immunological synapse; IBA from the LAT family node. Reason: LAT concentrates in TCR signaling assemblies at the T cell-APC contact; the PAINT node placement within the LAT clade is appropriate. Supporting Evidence: PMID:12646565 Transmembrane adaptor molecule LAT (linker for activation of T cells) forms a central scaffold for signaling protein complexes that accumulate in the vicinity of activated T cell antigen receptors (TCR). PMID:12646565 Taken together our data suggest a synergistic assembly of multimolecular TCR.LAT signal transduction complexes in T cell plasma membrane domains. |
| GO:0001772 immunological synapse | IDA PMID:12646565 Synergistic assembly of linker for activation of T cells sig... | ACCEPT | Summary: LAT, Grb2 and PLCgamma accumulate in TCR membrane domains imaged with GFP-tagged proteins. Reason: Direct imaging of LAT signaling assemblies at activated TCR contact sites supports immunological synapse localization. Supporting Evidence: PMID:12646565 We found that the phospholipase C gamma docking site of LAT and different Grb2/Gads docking sites function in an interdependent fashion and synergize to accumulate LAT, Grb2, and phospholipase C gamma in TCR signaling assemblies. PMID:12646565 Taken together our data suggest a synergistic assembly of multimolecular TCR.LAT signal transduction complexes in T cell plasma membrane domains. |
| GO:0001772 immunological synapse | IEA GO_REF:0000107 | ACCEPT | Summary: Ensembl Compara transfer of mouse Lat immunological synapse localization. Reason: Consistent with direct human evidence (PMID:12646565); 1:1 ortholog. Supporting Evidence: PMID:12646565 Taken together our data suggest a synergistic assembly of multimolecular TCR.LAT signal transduction complexes in T cell plasma membrane domains. |
| GO:0005515 protein binding | IPI PMID:10811803 Association of Grb2, Gads, and phospholipase C-gamma 1 with ... | MODIFY | Summary: IPI protein binding between LAT and PLCG1 (P19174) (PMID:10811803). Reason: The paper maps the LAT phosphotyrosines (Y132 for PLCG1) that dock SH2-domain effectors, which is the evidence for LAT's scaffold/adaptor function, not a bare binding activity. Bare protein binding is uninformative. Proposed replacements: signaling receptor complex adaptor activity Supporting Evidence: PMID:10811803 Upon T cell activation, LAT becomes highly phosphorylated on tyrosine residues, and Grb2, Gads, and phospholipase C (PLC)-gamma1 bind LAT via Src homology-2 domains. |
| GO:0005515 protein binding | IPI PMID:10811803 Association of Grb2, Gads, and phospholipase C-gamma 1 with ... | MODIFY | Summary: IPI protein binding between LAT and PIK3R1 (P27986) (PMID:10811803). Reason: Phospho-LAT docking of the p85 SH2 subunit is part of LAT's scaffold activity; replace bare binding with the adaptor term. Bare protein binding is uninformative. Proposed replacements: signaling receptor complex adaptor activity Supporting Evidence: PMID:10811803 Upon T cell activation, LAT becomes highly phosphorylated on tyrosine residues, and Grb2, Gads, and phospholipase C (PLC)-gamma1 bind LAT via Src homology-2 domains. |
| GO:0005515 protein binding | IPI PMID:10811803 Association of Grb2, Gads, and phospholipase C-gamma 1 with ... | MODIFY | Summary: IPI protein binding between LAT and GRB2 (P62993) (PMID:10811803). Reason: Phospho-LAT recruitment of GRB2 (and via it SOS1) is the core scaffold function of LAT; replace bare binding with the adaptor term. Bare protein binding is uninformative. Proposed replacements: signaling receptor complex adaptor activity Supporting Evidence: PMID:10811803 Upon T cell activation, LAT becomes highly phosphorylated on tyrosine residues, and Grb2, Gads, and phospholipase C (PLC)-gamma1 bind LAT via Src homology-2 domains. |
| GO:0005515 protein binding | IPI PMID:12186560 Phosphorylation of the linker for activation of T-cells by I... | MODIFY | Summary: IPI protein binding between LAT and VAV1 (P15498) (PMID:12186560). Reason: The paper maps LAT Y171/Y226 as docking sites for VAV1, i.e. LAT acting as a phosphotyrosine scaffold; replace bare binding with the adaptor term. Bare protein binding is uninformative. Proposed replacements: signaling receptor complex adaptor activity Supporting Evidence: PMID:12186560 we demonstrate that Y(171) and potentially Y(226) are docking sites for the Vav guanine nucleotide exchange factor. PMID:12186560 LAT is phosphorylated by protein tyrosine kinases (PTK) and binds to the adaptors Gads and Grb2, as well as to phospholipase Cgamma1 (PLCgamma1), thereby facilitating the recruitment of key signal transduction components to drive T-cell activation. |
| GO:0005515 protein binding | IPI PMID:12646565 Synergistic assembly of linker for activation of T cells sig... | REMOVE | Summary: IPI protein binding between LAT and ZAP70 (P43403) (PMID:12646565). Reason: ZAP70 is the kinase that phosphorylates LAT; the interaction is enzyme-substrate and does not indicate a LAT molecular function. Bare protein binding (GO:0005515) is uninformative about LAT function. Removal does not dispute the reported interaction; LAT's function as a phosphotyrosine-dependent scaffold is captured by GO:0030159 signaling receptor complex adaptor activity and GO:0035591 signaling adaptor activity. |
| GO:0005515 protein binding | IPI PMID:12857726 The tyrosine phosphatase 1B regulates linker for activation ... | REMOVE | Summary: IPI protein binding between LAT and PTPN1 (P18031) (PMID:12857726). Reason: PTP1B dephosphorylates phospho-LAT in platelets; LAT is the substrate, so the interaction does not describe a LAT activity. Bare protein binding (GO:0005515) is uninformative about LAT function. Removal does not dispute the reported interaction; LAT's function as a phosphotyrosine-dependent scaffold is captured by GO:0030159 signaling receptor complex adaptor activity and GO:0035591 signaling adaptor activity. Supporting Evidence: PMID:12857726 phospho-LAT appeared as a good substrate of activated PTP1B in vitro and these two proteins interacted upon platelet activation by FcgammaRIIa cross-linking. |
| GO:0005515 protein binding | IPI PMID:14722116 The importance of three membrane-distal tyrosines in the ada... | MODIFY | Summary: IPI protein binding between LAT and PLCG1 (P19174) (PMID:14722116). Reason: The curator's IPI records phosphotyrosine-dependent docking of an SH2-domain effector (PLCG1) on LAT, the same interaction captured from PMID:10811803. Only the abstract is cached, so the assay is accepted as curated. Bare protein binding is uninformative; the interaction is evidence for LAT's scaffold/adaptor activity, as for the other LAT-effector docking rows. Proposed replacements: signaling receptor complex adaptor activity Supporting Evidence: PMID:10811803 Upon T cell activation, LAT becomes highly phosphorylated on tyrosine residues, and Grb2, Gads, and phospholipase C (PLC)-gamma1 bind LAT via Src homology-2 domains. |
| GO:0005515 protein binding | IPI PMID:14722116 The importance of three membrane-distal tyrosines in the ada... | MODIFY | Summary: IPI protein binding between LAT and mouse Grb2 (Q60631) (PMID:14722116). Reason: The curator's IPI records phosphotyrosine-dependent docking of an SH2-domain effector (Grb2) on LAT, the same interaction captured from PMID:10811803. Only the abstract is cached, so the assay is accepted as curated. Bare protein binding is uninformative; the interaction is evidence for LAT's scaffold/adaptor activity, as for the other LAT-effector docking rows. Proposed replacements: signaling receptor complex adaptor activity Supporting Evidence: PMID:10811803 Upon T cell activation, LAT becomes highly phosphorylated on tyrosine residues, and Grb2, Gads, and phospholipase C (PLC)-gamma1 bind LAT via Src homology-2 domains. |
| GO:0005515 protein binding | IPI PMID:16938345 Evidence of LAT as a dual substrate for Lck and Syk in T lym... | REMOVE | Summary: IPI protein binding between LAT and LCK (P06239) (PMID:16938345). Reason: LCK is reported to phosphorylate LAT directly; this is an enzyme-substrate interaction, not a LAT function. Bare protein binding (GO:0005515) is uninformative about LAT function. Removal does not dispute the reported interaction; LAT's function as a phosphotyrosine-dependent scaffold is captured by GO:0030159 signaling receptor complex adaptor activity and GO:0035591 signaling adaptor activity. Supporting Evidence: PMID:16938345 In this study, we demonstrate that LAT serves as a dual substrate for both Lck and Syk kinases. |
| GO:0005515 protein binding | IPI PMID:16938345 Evidence of LAT as a dual substrate for Lck and Syk in T lym... | MODIFY | Summary: IPI protein binding between LAT and PLCG1 (P19174) (PMID:16938345). Reason: Phosphorylated LAT Y171/Y191 recruits Grb2, PLC-gamma1 and c-Cbl; this is the adaptor activity of LAT. Bare protein binding is uninformative. Proposed replacements: signaling receptor complex adaptor activity Supporting Evidence: PMID:16938345 Both Lck and Syk, phosphorylate the ITAM-like motifs on LAT at Y171Y191, which is essential for induction of the interaction of LAT with downstream signaling molecules such as Grb2, PLC-gamma1 and c-Cbl, and for activation of MAPK-ERK. |
| GO:0005515 protein binding | IPI PMID:16938345 Evidence of LAT as a dual substrate for Lck and Syk in T lym... | MODIFY | Summary: IPI protein binding between LAT and GRB2 (P62993) (PMID:16938345). Reason: Phosphorylated LAT Y171/Y191 recruits Grb2; this is the adaptor activity of LAT. Bare protein binding is uninformative. Proposed replacements: signaling receptor complex adaptor activity Supporting Evidence: PMID:16938345 Both Lck and Syk, phosphorylate the ITAM-like motifs on LAT at Y171Y191, which is essential for induction of the interaction of LAT with downstream signaling molecules such as Grb2, PLC-gamma1 and c-Cbl, and for activation of MAPK-ERK. |
| GO:0005515 protein binding | IPI PMID:24642916 Fine specificity and molecular competition in SLAM family re... | REMOVE | Summary: IPI protein binding between LAT and PLCG1 (P19174) (PMID:24642916). Reason: A LAT pY132 phosphopeptide was used only as a positive control for PLCgamma SH2 binding in a SLAM-family study; the phosphotyrosine-reading activity belongs to PLCG1. Bare protein binding (GO:0005515) is uninformative about LAT function. Removal does not dispute the reported interaction; LAT's function as a phosphotyrosine-dependent scaffold is captured by GO:0030159 signaling receptor complex adaptor activity and GO:0035591 signaling adaptor activity. Supporting Evidence: PMID:24642916 PLCΞ³1 and PLCΞ³2 displayed similar specificity for EAT-2 and for the positive control phosphopeptide from LAT. |
| GO:0005515 protein binding | IPI PMID:24658140 The mammalian-membrane two-hybrid assay (MaMTH) for probing ... | REMOVE | Summary: IPI protein binding between LAT and EGFR (P00533) (PMID:24658140). Reason: High-throughput membrane two-hybrid (MaMTH) screen hit with no functional follow-up for LAT; EGFR-LAT has no established physiological role. Bare protein binding (GO:0005515) is uninformative about LAT function. Removal does not dispute the reported interaction; LAT's function as a phosphotyrosine-dependent scaffold is captured by GO:0030159 signaling receptor complex adaptor activity and GO:0035591 signaling adaptor activity. |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | REMOVE | Summary: IPI protein binding between LAT and SGTA (O43765) (PMID:25416956). Reason: Proteome-scale yeast two-hybrid hit (HuRI); SGTA is a cochaperone of tail-anchored/hydrophobic membrane proteins and the interaction is unlikely to reflect a LAT function. Bare protein binding (GO:0005515) is uninformative about LAT function. Removal does not dispute the reported interaction; LAT's function as a phosphotyrosine-dependent scaffold is captured by GO:0030159 signaling receptor complex adaptor activity and GO:0035591 signaling adaptor activity. |
| GO:0005515 protein binding | IPI PMID:31980649 Extensive rewiring of the EGFR network in colorectal cancer ... | REMOVE | Summary: IPI protein binding between LAT and EGFR (P00533) (PMID:31980649). Reason: EGFR interactome proteomics in colorectal cancer cells; no evidence this reflects a LAT function in its native lymphoid/myeloid context. Bare protein binding (GO:0005515) is uninformative about LAT function. Removal does not dispute the reported interaction; LAT's function as a phosphotyrosine-dependent scaffold is captured by GO:0030159 signaling receptor complex adaptor activity and GO:0035591 signaling adaptor activity. |
| GO:0005515 protein binding | IPI PMID:9489702 LAT: the ZAP-70 tyrosine kinase substrate that links T cell ... | MODIFY | Summary: IPI protein binding between LAT and PLCG1 (P19174) (PMID:9489702). Reason: The founding LAT paper shows ZAP70/Syk phosphorylation of LAT leads to recruitment of multiple signaling molecules including PLCG1 - the adaptor activity. Bare protein binding is uninformative. Proposed replacements: signaling receptor complex adaptor activity Supporting Evidence: PMID:9489702 We show that this protein is phosphorylated by ZAP-70/Syk protein tyrosine kinases leading to recruitment of multiple signaling molecules. |
| GO:0005515 protein binding | IPI PMID:9489702 LAT: the ZAP-70 tyrosine kinase substrate that links T cell ... | MODIFY | Summary: IPI protein binding between LAT and GRB2 (P62993) (PMID:9489702). Reason: The founding LAT paper shows ZAP70/Syk phosphorylation of LAT leads to recruitment of Grb2 and other signaling molecules - the adaptor activity. Bare protein binding is uninformative. Proposed replacements: signaling receptor complex adaptor activity Supporting Evidence: PMID:9489702 We show that this protein is phosphorylated by ZAP-70/Syk protein tyrosine kinases leading to recruitment of multiple signaling molecules. |
| GO:0005886 plasma membrane | IDA GO_REF:0000052 | ACCEPT | Summary: Human Protein Atlas immunofluorescence localizes LAT to the plasma membrane. Reason: LAT is a single-pass (type III) plasma membrane protein; consistent with all other evidence. Supporting Evidence: PMID:9729044 Although the LAT transmembrane domain is sufficient for membrane localization, palmitoylation at C26 and C29 is essential for efficient partitioning into GEMs. |
| GO:0005886 plasma membrane | IDA PMID:11368773 Mapping the Zap-70 phosphorylation sites on LAT (linker for ... | ACCEPT | Summary: Plasma membrane recruitment of LAT signalling complexes. Reason: LAT acts at the plasma membrane where it nucleates signaling complexes. Supporting Evidence: PMID:11368773 we reconstituted the LAT signalling pathway by demonstrating that a direct tyrosine phosphorylation of LAT with activated protein-tyrosine kinase Zap70 is necessary and sufficient for the association and activation of signalling proteins. |
| GO:0005886 plasma membrane | IDA PMID:9729044 LAT palmitoylation: its essential role in membrane microdoma... | ACCEPT | Summary: LAT transmembrane domain and palmitoylation direct it to the plasma membrane and GEM/raft domains. Reason: Direct demonstration of LAT plasma membrane localization. Supporting Evidence: PMID:9729044 We demonstrate that human LAT is palmitoylated and that palmitoylated LAT predominantly localizes into glycolipid-enriched microdomains (GEMs). PMID:9729044 Although the LAT transmembrane domain is sufficient for membrane localization, palmitoylation at C26 and C29 is essential for efficient partitioning into GEMs. |
| GO:0005886 plasma membrane | IEA GO_REF:0000044 | ACCEPT | Summary: UniProt subcellular location mapping (cell membrane). Reason: Correct; LAT is an integral plasma membrane protein. Supporting Evidence: PMID:9489702 Deduced amino acid sequence identifies a novel integral membrane protein containing multiple potential tyrosine phosphorylation sites. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-202212 | ACCEPT | Summary: Reactome reaction (Reactome:R-HSA-202212) places LAT at the plasma membrane as part of TCR, FCERI or GPVI signaling complexes. Reason: Plasma membrane localization is correct for LAT regardless of the particular Reactome reaction; LAT is a transmembrane scaffold that nucleates these membrane-proximal complexes. Supporting Evidence: PMID:9729044 Although the LAT transmembrane domain is sufficient for membrane localization, palmitoylation at C26 and C29 is essential for efficient partitioning into GEMs. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-202216 | ACCEPT | Summary: Reactome reaction (Reactome:R-HSA-202216) places LAT at the plasma membrane as part of TCR, FCERI or GPVI signaling complexes. Reason: Plasma membrane localization is correct for LAT regardless of the particular Reactome reaction; LAT is a transmembrane scaffold that nucleates these membrane-proximal complexes. Supporting Evidence: PMID:9729044 Although the LAT transmembrane domain is sufficient for membrane localization, palmitoylation at C26 and C29 is essential for efficient partitioning into GEMs. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-202241 | ACCEPT | Summary: Reactome reaction (Reactome:R-HSA-202241) places LAT at the plasma membrane as part of TCR, FCERI or GPVI signaling complexes. Reason: Plasma membrane localization is correct for LAT regardless of the particular Reactome reaction; LAT is a transmembrane scaffold that nucleates these membrane-proximal complexes. Supporting Evidence: PMID:9729044 Although the LAT transmembrane domain is sufficient for membrane localization, palmitoylation at C26 and C29 is essential for efficient partitioning into GEMs. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-202245 | ACCEPT | Summary: Reactome reaction (Reactome:R-HSA-202245) places LAT at the plasma membrane as part of TCR, FCERI or GPVI signaling complexes. Reason: Plasma membrane localization is correct for LAT regardless of the particular Reactome reaction; LAT is a transmembrane scaffold that nucleates these membrane-proximal complexes. Supporting Evidence: PMID:9729044 Although the LAT transmembrane domain is sufficient for membrane localization, palmitoylation at C26 and C29 is essential for efficient partitioning into GEMs. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-202248 | ACCEPT | Summary: Reactome reaction (Reactome:R-HSA-202248) places LAT at the plasma membrane as part of TCR, FCERI or GPVI signaling complexes. Reason: Plasma membrane localization is correct for LAT regardless of the particular Reactome reaction; LAT is a transmembrane scaffold that nucleates these membrane-proximal complexes. Supporting Evidence: PMID:9729044 Although the LAT transmembrane domain is sufficient for membrane localization, palmitoylation at C26 and C29 is essential for efficient partitioning into GEMs. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-202325 | ACCEPT | Summary: Reactome reaction (Reactome:R-HSA-202325) places LAT at the plasma membrane as part of TCR, FCERI or GPVI signaling complexes. Reason: Plasma membrane localization is correct for LAT regardless of the particular Reactome reaction; LAT is a transmembrane scaffold that nucleates these membrane-proximal complexes. Supporting Evidence: PMID:9729044 Although the LAT transmembrane domain is sufficient for membrane localization, palmitoylation at C26 and C29 is essential for efficient partitioning into GEMs. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-202331 | ACCEPT | Summary: Reactome reaction (Reactome:R-HSA-202331) places LAT at the plasma membrane as part of TCR, FCERI or GPVI signaling complexes. Reason: Plasma membrane localization is correct for LAT regardless of the particular Reactome reaction; LAT is a transmembrane scaffold that nucleates these membrane-proximal complexes. Supporting Evidence: PMID:9729044 Although the LAT transmembrane domain is sufficient for membrane localization, palmitoylation at C26 and C29 is essential for efficient partitioning into GEMs. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-202375 | ACCEPT | Summary: Reactome reaction (Reactome:R-HSA-202375) places LAT at the plasma membrane as part of TCR, FCERI or GPVI signaling complexes. Reason: Plasma membrane localization is correct for LAT regardless of the particular Reactome reaction; LAT is a transmembrane scaffold that nucleates these membrane-proximal complexes. Supporting Evidence: PMID:9729044 Although the LAT transmembrane domain is sufficient for membrane localization, palmitoylation at C26 and C29 is essential for efficient partitioning into GEMs. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-213406 | ACCEPT | Summary: Reactome reaction (Reactome:R-HSA-213406) places LAT at the plasma membrane as part of TCR, FCERI or GPVI signaling complexes. Reason: Plasma membrane localization is correct for LAT regardless of the particular Reactome reaction; LAT is a transmembrane scaffold that nucleates these membrane-proximal complexes. Supporting Evidence: PMID:9729044 Although the LAT transmembrane domain is sufficient for membrane localization, palmitoylation at C26 and C29 is essential for efficient partitioning into GEMs. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-213407 | ACCEPT | Summary: Reactome reaction (Reactome:R-HSA-213407) places LAT at the plasma membrane as part of TCR, FCERI or GPVI signaling complexes. Reason: Plasma membrane localization is correct for LAT regardless of the particular Reactome reaction; LAT is a transmembrane scaffold that nucleates these membrane-proximal complexes. Supporting Evidence: PMID:9729044 Although the LAT transmembrane domain is sufficient for membrane localization, palmitoylation at C26 and C29 is essential for efficient partitioning into GEMs. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-2395801 | ACCEPT | Summary: Reactome reaction (Reactome:R-HSA-2395801) places LAT at the plasma membrane as part of TCR, FCERI or GPVI signaling complexes. Reason: Plasma membrane localization is correct for LAT regardless of the particular Reactome reaction; LAT is a transmembrane scaffold that nucleates these membrane-proximal complexes. Supporting Evidence: PMID:9729044 Although the LAT transmembrane domain is sufficient for membrane localization, palmitoylation at C26 and C29 is essential for efficient partitioning into GEMs. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-2396561 | ACCEPT | Summary: Reactome reaction (Reactome:R-HSA-2396561) places LAT at the plasma membrane as part of TCR, FCERI or GPVI signaling complexes. Reason: Plasma membrane localization is correct for LAT regardless of the particular Reactome reaction; LAT is a transmembrane scaffold that nucleates these membrane-proximal complexes. Supporting Evidence: PMID:9729044 Although the LAT transmembrane domain is sufficient for membrane localization, palmitoylation at C26 and C29 is essential for efficient partitioning into GEMs. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-2396594 | ACCEPT | Summary: Reactome reaction (Reactome:R-HSA-2396594) places LAT at the plasma membrane as part of TCR, FCERI or GPVI signaling complexes. Reason: Plasma membrane localization is correct for LAT regardless of the particular Reactome reaction; LAT is a transmembrane scaffold that nucleates these membrane-proximal complexes. Supporting Evidence: PMID:9729044 Although the LAT transmembrane domain is sufficient for membrane localization, palmitoylation at C26 and C29 is essential for efficient partitioning into GEMs. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-2396599 | ACCEPT | Summary: Reactome reaction (Reactome:R-HSA-2396599) places LAT at the plasma membrane as part of TCR, FCERI or GPVI signaling complexes. Reason: Plasma membrane localization is correct for LAT regardless of the particular Reactome reaction; LAT is a transmembrane scaffold that nucleates these membrane-proximal complexes. Supporting Evidence: PMID:9729044 Although the LAT transmembrane domain is sufficient for membrane localization, palmitoylation at C26 and C29 is essential for efficient partitioning into GEMs. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-2396606 | ACCEPT | Summary: Reactome reaction (Reactome:R-HSA-2396606) places LAT at the plasma membrane as part of TCR, FCERI or GPVI signaling complexes. Reason: Plasma membrane localization is correct for LAT regardless of the particular Reactome reaction; LAT is a transmembrane scaffold that nucleates these membrane-proximal complexes. Supporting Evidence: PMID:9729044 Although the LAT transmembrane domain is sufficient for membrane localization, palmitoylation at C26 and C29 is essential for efficient partitioning into GEMs. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-2424476 | ACCEPT | Summary: Reactome reaction (Reactome:R-HSA-2424476) places LAT at the plasma membrane as part of TCR, FCERI or GPVI signaling complexes. Reason: Plasma membrane localization is correct for LAT regardless of the particular Reactome reaction; LAT is a transmembrane scaffold that nucleates these membrane-proximal complexes. Supporting Evidence: PMID:9729044 Although the LAT transmembrane domain is sufficient for membrane localization, palmitoylation at C26 and C29 is essential for efficient partitioning into GEMs. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-2424477 | ACCEPT | Summary: Reactome reaction (Reactome:R-HSA-2424477) places LAT at the plasma membrane as part of TCR, FCERI or GPVI signaling complexes. Reason: Plasma membrane localization is correct for LAT regardless of the particular Reactome reaction; LAT is a transmembrane scaffold that nucleates these membrane-proximal complexes. Supporting Evidence: PMID:9729044 Although the LAT transmembrane domain is sufficient for membrane localization, palmitoylation at C26 and C29 is essential for efficient partitioning into GEMs. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-2424481 | ACCEPT | Summary: Reactome reaction (Reactome:R-HSA-2424481) places LAT at the plasma membrane as part of TCR, FCERI or GPVI signaling complexes. Reason: Plasma membrane localization is correct for LAT regardless of the particular Reactome reaction; LAT is a transmembrane scaffold that nucleates these membrane-proximal complexes. Supporting Evidence: PMID:9729044 Although the LAT transmembrane domain is sufficient for membrane localization, palmitoylation at C26 and C29 is essential for efficient partitioning into GEMs. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-2424484 | ACCEPT | Summary: Reactome reaction (Reactome:R-HSA-2424484) places LAT at the plasma membrane as part of TCR, FCERI or GPVI signaling complexes. Reason: Plasma membrane localization is correct for LAT regardless of the particular Reactome reaction; LAT is a transmembrane scaffold that nucleates these membrane-proximal complexes. Supporting Evidence: PMID:9729044 Although the LAT transmembrane domain is sufficient for membrane localization, palmitoylation at C26 and C29 is essential for efficient partitioning into GEMs. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-2424485 | ACCEPT | Summary: Reactome reaction (Reactome:R-HSA-2424485) places LAT at the plasma membrane as part of TCR, FCERI or GPVI signaling complexes. Reason: Plasma membrane localization is correct for LAT regardless of the particular Reactome reaction; LAT is a transmembrane scaffold that nucleates these membrane-proximal complexes. Supporting Evidence: PMID:9729044 Although the LAT transmembrane domain is sufficient for membrane localization, palmitoylation at C26 and C29 is essential for efficient partitioning into GEMs. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-2424486 | ACCEPT | Summary: Reactome reaction (Reactome:R-HSA-2424486) places LAT at the plasma membrane as part of TCR, FCERI or GPVI signaling complexes. Reason: Plasma membrane localization is correct for LAT regardless of the particular Reactome reaction; LAT is a transmembrane scaffold that nucleates these membrane-proximal complexes. Supporting Evidence: PMID:9729044 Although the LAT transmembrane domain is sufficient for membrane localization, palmitoylation at C26 and C29 is essential for efficient partitioning into GEMs. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-2424487 | ACCEPT | Summary: Reactome reaction (Reactome:R-HSA-2424487) places LAT at the plasma membrane as part of TCR, FCERI or GPVI signaling complexes. Reason: Plasma membrane localization is correct for LAT regardless of the particular Reactome reaction; LAT is a transmembrane scaffold that nucleates these membrane-proximal complexes. Supporting Evidence: PMID:9729044 Although the LAT transmembrane domain is sufficient for membrane localization, palmitoylation at C26 and C29 is essential for efficient partitioning into GEMs. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-2730833 | ACCEPT | Summary: Reactome reaction (Reactome:R-HSA-2730833) places LAT at the plasma membrane as part of TCR, FCERI or GPVI signaling complexes. Reason: Plasma membrane localization is correct for LAT regardless of the particular Reactome reaction; LAT is a transmembrane scaffold that nucleates these membrane-proximal complexes. Supporting Evidence: PMID:9729044 Although the LAT transmembrane domain is sufficient for membrane localization, palmitoylation at C26 and C29 is essential for efficient partitioning into GEMs. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-2730840 | ACCEPT | Summary: Reactome reaction (Reactome:R-HSA-2730840) places LAT at the plasma membrane as part of TCR, FCERI or GPVI signaling complexes. Reason: Plasma membrane localization is correct for LAT regardless of the particular Reactome reaction; LAT is a transmembrane scaffold that nucleates these membrane-proximal complexes. Supporting Evidence: PMID:9729044 Although the LAT transmembrane domain is sufficient for membrane localization, palmitoylation at C26 and C29 is essential for efficient partitioning into GEMs. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-2730841 | ACCEPT | Summary: Reactome reaction (Reactome:R-HSA-2730841) places LAT at the plasma membrane as part of TCR, FCERI or GPVI signaling complexes. Reason: Plasma membrane localization is correct for LAT regardless of the particular Reactome reaction; LAT is a transmembrane scaffold that nucleates these membrane-proximal complexes. Supporting Evidence: PMID:9729044 Although the LAT transmembrane domain is sufficient for membrane localization, palmitoylation at C26 and C29 is essential for efficient partitioning into GEMs. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-2730843 | ACCEPT | Summary: Reactome reaction (Reactome:R-HSA-2730843) places LAT at the plasma membrane as part of TCR, FCERI or GPVI signaling complexes. Reason: Plasma membrane localization is correct for LAT regardless of the particular Reactome reaction; LAT is a transmembrane scaffold that nucleates these membrane-proximal complexes. Supporting Evidence: PMID:9729044 Although the LAT transmembrane domain is sufficient for membrane localization, palmitoylation at C26 and C29 is essential for efficient partitioning into GEMs. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-2730847 | ACCEPT | Summary: Reactome reaction (Reactome:R-HSA-2730847) places LAT at the plasma membrane as part of TCR, FCERI or GPVI signaling complexes. Reason: Plasma membrane localization is correct for LAT regardless of the particular Reactome reaction; LAT is a transmembrane scaffold that nucleates these membrane-proximal complexes. Supporting Evidence: PMID:9729044 Although the LAT transmembrane domain is sufficient for membrane localization, palmitoylation at C26 and C29 is essential for efficient partitioning into GEMs. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-2730851 | ACCEPT | Summary: Reactome reaction (Reactome:R-HSA-2730851) places LAT at the plasma membrane as part of TCR, FCERI or GPVI signaling complexes. Reason: Plasma membrane localization is correct for LAT regardless of the particular Reactome reaction; LAT is a transmembrane scaffold that nucleates these membrane-proximal complexes. Supporting Evidence: PMID:9729044 Although the LAT transmembrane domain is sufficient for membrane localization, palmitoylation at C26 and C29 is essential for efficient partitioning into GEMs. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-2730856 | ACCEPT | Summary: Reactome reaction (Reactome:R-HSA-2730856) places LAT at the plasma membrane as part of TCR, FCERI or GPVI signaling complexes. Reason: Plasma membrane localization is correct for LAT regardless of the particular Reactome reaction; LAT is a transmembrane scaffold that nucleates these membrane-proximal complexes. Supporting Evidence: PMID:9729044 Although the LAT transmembrane domain is sufficient for membrane localization, palmitoylation at C26 and C29 is essential for efficient partitioning into GEMs. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-2730858 | ACCEPT | Summary: Reactome reaction (Reactome:R-HSA-2730858) places LAT at the plasma membrane as part of TCR, FCERI or GPVI signaling complexes. Reason: Plasma membrane localization is correct for LAT regardless of the particular Reactome reaction; LAT is a transmembrane scaffold that nucleates these membrane-proximal complexes. Supporting Evidence: PMID:9729044 Although the LAT transmembrane domain is sufficient for membrane localization, palmitoylation at C26 and C29 is essential for efficient partitioning into GEMs. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-2730889 | ACCEPT | Summary: Reactome reaction (Reactome:R-HSA-2730889) places LAT at the plasma membrane as part of TCR, FCERI or GPVI signaling complexes. Reason: Plasma membrane localization is correct for LAT regardless of the particular Reactome reaction; LAT is a transmembrane scaffold that nucleates these membrane-proximal complexes. Supporting Evidence: PMID:9729044 Although the LAT transmembrane domain is sufficient for membrane localization, palmitoylation at C26 and C29 is essential for efficient partitioning into GEMs. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-2730892 | ACCEPT | Summary: Reactome reaction (Reactome:R-HSA-2730892) places LAT at the plasma membrane as part of TCR, FCERI or GPVI signaling complexes. Reason: Plasma membrane localization is correct for LAT regardless of the particular Reactome reaction; LAT is a transmembrane scaffold that nucleates these membrane-proximal complexes. Supporting Evidence: PMID:9729044 Although the LAT transmembrane domain is sufficient for membrane localization, palmitoylation at C26 and C29 is essential for efficient partitioning into GEMs. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-434836 | ACCEPT | Summary: Reactome reaction (Reactome:R-HSA-434836) places LAT at the plasma membrane as part of TCR, FCERI or GPVI signaling complexes. Reason: Plasma membrane localization is correct for LAT regardless of the particular Reactome reaction; LAT is a transmembrane scaffold that nucleates these membrane-proximal complexes. Supporting Evidence: PMID:9729044 Although the LAT transmembrane domain is sufficient for membrane localization, palmitoylation at C26 and C29 is essential for efficient partitioning into GEMs. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-5672965 | ACCEPT | Summary: Reactome reaction (Reactome:R-HSA-5672965) places LAT at the plasma membrane as part of TCR, FCERI or GPVI signaling complexes. Reason: Plasma membrane localization is correct for LAT regardless of the particular Reactome reaction; LAT is a transmembrane scaffold that nucleates these membrane-proximal complexes. Supporting Evidence: PMID:9729044 Although the LAT transmembrane domain is sufficient for membrane localization, palmitoylation at C26 and C29 is essential for efficient partitioning into GEMs. |
| GO:0005911 cell-cell junction | IEA GO_REF:0000107 | MODIFY | Summary: Ensembl Compara transfer of mouse Lat cell-cell junction localization (from an Rltpr/CD28 study at the T cell immunological synapse). Reason: The source mouse annotation concerns the T cell-APC contact (immunological synapse), which is not a cell-cell junction in the epithelial sense; immunological synapse is the accurate term and is already supported by direct human evidence. Proposed replacements: immunological synapse Supporting Evidence: PMID:23793062 Engagement of TCR-CD28 at the immunological synapse resulted in the colocalization of CD28 with both wild-type and mutant Rltpr proteins. PMID:12646565 Taken together our data suggest a synergistic assembly of multimolecular TCR.LAT signal transduction complexes in T cell plasma membrane domains. |
| GO:0006954 inflammatory response | IBA GO_REF:0000033 | MARK AS OVER ANNOTATED | Summary: IBA for inflammatory response, seeded from mouse Lat IMP data (LatY136F/Lat3YF knock-in mice). Reason: The source phenotype is a T cell lymphoproliferative disorder with allergic-type inflammation in LAT tyrosine mutant mice; this reflects dysregulated T cell signaling (necessity/ phenotype), not LAT executing an inflammatory response. LAT's process role is captured by T cell receptor and Fc receptor signaling pathways. Propagation Review Root cause: SOURCE WEAK OR INFERRED Failure modes: ROLE CONFLATION CONTEXT OR TISSUE MISMATCH Sources checked: PANTHER:PTN008356078 SOURCE WEAK OR INFERRED LAT-clade node carrying the inflammatory response IBD; the node placement is fine for the family but the asserted process is a phenotype-level outcome. MGI:MGI:1342293 SOURCE WEAK OR INFERRED Mouse Lat IMP (PMID:16002666) is from LatY136F/Lat3YF knock-in mice whose dysregulated T cells cause allergic-type inflammation; this records necessity/phenotype, not LAT performing an inflammatory response. Supporting Evidence: PMID:16002666 Mice with mutations of distinct LAT tyrosine residues (LatY136F and Lat3YF) develop lymphoproliferative disorders involving TCR alphabeta or gammadelta T cells that trigger symptoms resembling allergic inflammation. |
| GO:0006955 immune response | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: IBA for immune response. Reason: True but very general; LAT's specific role is captured by T cell receptor signaling pathway and Fc receptor signaling terms. Supporting Evidence: PMID:10204488 LAT is thus critical to both T cell activation and development. |
| GO:0006955 immune response | IDA PMID:15100278 Control of TCR-mediated activation of beta 1 integrins by th... | KEEP AS NON CORE | Summary: Immune response based on TCR-induced beta1 integrin activation requiring LAT. Reason: Correct but very general; more informative process terms exist. Supporting Evidence: PMID:15100278 CD3/TCR signaling to beta(1) integrins is defective in LAT-deficient Jurkat T cells, and can be restored with expression of wild-type LAT. |
| GO:0007165 signal transduction | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro2GO signal transduction. Reason: Broad but correct for a signaling adaptor. Supporting Evidence: PMID:10811803 In LAT-deficient mutant Jurkat cells, TCR engagement fails to induce ERK activation, Ca(2+) flux, and activation of AP-1 and NF-AT. |
| GO:0007229 integrin-mediated signaling pathway | IDA PMID:15100278 Control of TCR-mediated activation of beta 1 integrins by th... | MODIFY | Summary: LAT Y171/Y191 required for TCR-induced activation of beta1 integrins (inside-out signaling) in Jurkat cells. Reason: GO:0007229 integrin-mediated signaling pathway describes signaling initiated by integrins (outside-in). The paper shows TCR-to-integrin inside-out activation, for which positive regulation of integrin activation is the correct term; non-core relative to TCR signaling. Proposed replacements: positive regulation of integrin activation Supporting Evidence: PMID:15100278 CD3/TCR signaling to beta(1) integrins is defective in LAT-deficient Jurkat T cells, and can be restored with expression of wild-type LAT. |
| GO:0007265 Ras protein signal transduction | IMP PMID:12646565 Synergistic assembly of linker for activation of T cells sig... | ACCEPT | Summary: LAT Grb2/Gads and PLCgamma docking sites synergize to build TCR signaling assemblies; LAT recruits Grb2-SOS and PLCG1 (RasGRP) to activate Ras. Reason: LAT directly scaffolds the Grb2-SOS and PLCG1 arms that activate Ras downstream of the TCR; Y132 is required for Ras pathway activation. Supporting Evidence: PMID:12646565 We found that the phospholipase C gamma docking site of LAT and different Grb2/Gads docking sites function in an interdependent fashion and synergize to accumulate LAT, Grb2, and phospholipase C gamma in TCR signaling assemblies. PMID:11368773 we demonstrate that Tyr(191) and Tyr(171) are required for T-cell activation and Tyr(132) is required for the activation of PLCgamma1 and Ras signalling pathways. |
| GO:0008180 COP9 signalosome | IEA GO_REF:0000107 | MODIFY | Summary: Ensembl Compara transfer of mouse Lat 'COP9 signalosome', itself a UniProt IDA from a Tespa1 paper describing the TCR signalosome. Reason: The source paper (PMID:22561606) describes the TCR signalosome, the LAT-nucleated signaling complex. COP9 signalosome (GO:0008180) is the unrelated CSN deneddylase complex; the annotation appears to be a signalosome term-selection error. LAT defines the TCR signalosome (GO:0036398). Proposed replacements: TCR signalosome Supporting Evidence: PMID:22561606 Our findings demonstrate that Tespa1 is a component of the TCR signalosome PMID:12646565 Taken together our data suggest a synergistic assembly of multimolecular TCR.LAT signal transduction complexes in T cell plasma membrane domains. |
| GO:0008180 COP9 signalosome | ISS GO_REF:0000024 | MODIFY | Summary: ISS from mouse Lat 'COP9 signalosome' (UniProt, source PMID:22561606). Reason: Same source as the IEA row: the Tespa1 paper concerns the TCR signalosome, not the COP9 (CSN) deneddylation complex. Replace with TCR signalosome. Proposed replacements: TCR signalosome Supporting Evidence: PMID:22561606 Our findings demonstrate that Tespa1 is a component of the TCR signalosome |
| GO:0016020 membrane | IDA PMID:12646565 Synergistic assembly of linker for activation of T cells sig... | ACCEPT | Summary: LAT in immunoisolated T cell plasma membrane domains. Reason: Correct; plasma membrane is the more specific term. Supporting Evidence: PMID:12646565 Taken together our data suggest a synergistic assembly of multimolecular TCR.LAT signal transduction complexes in T cell plasma membrane domains. |
| GO:0016020 membrane | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro2GO membrane. Reason: Correct but general. Supporting Evidence: PMID:9489702 Deduced amino acid sequence identifies a novel integral membrane protein containing multiple potential tyrosine phosphorylation sites. |
| GO:0019722 calcium-mediated signaling | IMP PMID:12646565 Synergistic assembly of linker for activation of T cells sig... | KEEP AS NON CORE | Summary: LAT PLCgamma docking site required for TCR-induced calcium signaling. Reason: LAT recruits PLCG1, which generates IP3 for calcium release; LAT acts upstream of the calcium second-messenger step rather than within it. Kept as non-core. Supporting Evidence: PMID:10811803 Mutation of Tyr(132) affected calcium flux and blocked Erk and NF-AT activation. |
| GO:0019901 protein kinase binding | IPI PMID:12186560 Phosphorylation of the linker for activation of T-cells by I... | MARK AS OVER ANNOTATED | Summary: IPI protein kinase binding with ITK (Q08881). Reason: ITK (and ZAP70) phosphorylate LAT; binding reflects a kinase-substrate relationship and is not a molecular function of LAT. The downstream consequence (Vav recruitment) is captured by the adaptor activity. Supporting Evidence: PMID:12186560 These data indicate that kinases from distinct PTK families are likely responsible for LAT phosphorylation following T-cell activation and that Itk kinase activity promotes recruitment of Vav to LAT. |
| GO:0030159 signaling receptor complex adaptor activity | IBA GO_REF:0000033 | ACCEPT | Summary: IBA signaling receptor complex adaptor activity. Reason: LAT provides the physical platform for assembly of the TCR signalosome; this is its core MF, inherited within the LAT clade. Supporting Evidence: PMID:12646565 Transmembrane adaptor molecule LAT (linker for activation of T cells) forms a central scaffold for signaling protein complexes that accumulate in the vicinity of activated T cell antigen receptors (TCR). |
| GO:0030159 signaling receptor complex adaptor activity | IDA PMID:9489702 LAT: the ZAP-70 tyrosine kinase substrate that links T cell ... | ACCEPT | Summary: LAT, phosphorylated by ZAP70/Syk, recruits multiple signaling molecules. Reason: Core molecular function of LAT. Supporting Evidence: PMID:9489702 We show that this protein is phosphorylated by ZAP-70/Syk protein tyrosine kinases leading to recruitment of multiple signaling molecules. PMID:9489702 Its function is demonstrated by inhibition of T cell activation following overexpression of a mutant form lacking critical tyrosine residues. |
| GO:0035556 intracellular signal transduction | IDA PMID:12646565 Synergistic assembly of linker for activation of T cells sig... | ACCEPT | Summary: LAT signaling complexes in T cell plasma membrane domains. Reason: Broad but correct. Supporting Evidence: PMID:12646565 Taken together our data suggest a synergistic assembly of multimolecular TCR.LAT signal transduction complexes in T cell plasma membrane domains. |
| GO:0035591 signaling adaptor activity | IDA PMID:9489702 LAT: the ZAP-70 tyrosine kinase substrate that links T cell ... | ACCEPT | Summary: LAT as a signaling adaptor linking ZAP70 to PLCG1, GRB2 and other effectors. Reason: LAT has no catalytic activity and functions to bring together signaling molecules; this parent adaptor term is correct. Supporting Evidence: PMID:9489702 We show that this protein is phosphorylated by ZAP-70/Syk protein tyrosine kinases leading to recruitment of multiple signaling molecules. |
| GO:0036398 TCR signalosome | IBA GO_REF:0000033 | ACCEPT | Summary: IBA TCR signalosome. Reason: LAT is the defining scaffold of the TCR signalosome. Supporting Evidence: PMID:12646565 Taken together our data suggest a synergistic assembly of multimolecular TCR.LAT signal transduction complexes in T cell plasma membrane domains. |
| GO:0042110 T cell activation | IDA PMID:11368773 Mapping the Zap-70 phosphorylation sites on LAT (linker for ... | KEEP AS NON CORE | Summary: LAT Y171/Y191 required for T cell activation. Reason: LAT acts in T cell activation through TCR signaling; T cell activation is a broad downstream outcome, so kept as non-core with TCR signaling as the core process. Supporting Evidence: PMID:11368773 we demonstrate that Tyr(191) and Tyr(171) are required for T-cell activation and Tyr(132) is required for the activation of PLCgamma1 and Ras signalling pathways. |
| GO:0042110 T cell activation | TAS PMID:12186560 Phosphorylation of the linker for activation of T-cells by I... | KEEP AS NON CORE | Summary: TAS T cell activation. Reason: As above; broad downstream outcome. Supporting Evidence: PMID:12186560 LAT is phosphorylated by protein tyrosine kinases (PTK) and binds to the adaptors Gads and Grb2, as well as to phospholipase Cgamma1 (PLCgamma1), thereby facilitating the recruitment of key signal transduction components to drive T-cell activation. |
| GO:0043410 positive regulation of MAPK cascade | IDA PMID:11368773 Mapping the Zap-70 phosphorylation sites on LAT (linker for ... | KEEP AS NON CORE | Summary: LAT tyrosines required for Ras/MAPK activation upon TCR stimulation. Reason: LAT's Grb2-SOS and PLCG1 docking positively regulate MAPK signaling; correct but downstream of the core TCR signaling role. Supporting Evidence: PMID:11368773 we demonstrate that Tyr(191) and Tyr(171) are required for T-cell activation and Tyr(132) is required for the activation of PLCgamma1 and Ras signalling pathways. |
| GO:0045121 membrane raft | TAS PMID:12496963 CD45 ectodomain controls interaction with GEMs and Lck activ... | ACCEPT | Summary: TAS membrane raft (CD45 ectodomain paper). Reason: LAT localization to GEMs/rafts is directly established (PMID:9729044); the location is correct even though this paper is about CD45. Supporting Evidence: PMID:9729044 We demonstrate that human LAT is palmitoylated and that palmitoylated LAT predominantly localizes into glycolipid-enriched microdomains (GEMs). |
| GO:0045121 membrane raft | TAS PMID:14722116 The importance of three membrane-distal tyrosines in the ada... | ACCEPT | Summary: TAS membrane raft (NTAL/LAB paper). Reason: LAT is a palmitoylated raft-resident adaptor. Supporting Evidence: PMID:12186560 The linker for activation of T-cells (LAT) is a palmitoylated integral membrane adaptor protein that resides in lipid membrane rafts PMID:9729044 We demonstrate that human LAT is palmitoylated and that palmitoylated LAT predominantly localizes into glycolipid-enriched microdomains (GEMs). |
| 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 from a microarray study of LAT-deficient Jurkat cells and basal RAG repression. Reason: The paper shows basal tonic signaling requiring LAT and SLP-76 represses RAG expression via Erk and Abl; expression-pattern evidence does not show LAT regulating kinase activity, and LAT's contribution is as a scaffold within TCR signaling. Supporting Evidence: PMID:14624253 We hypothesized that normal RAG gene expression in resting cells is held in check by a basal signal that requires both LAT and SLP-76. |
| GO:0050852 T cell receptor signaling pathway | IBA GO_REF:0000033 | ACCEPT | Summary: IBA T cell receptor signaling pathway. Reason: Core process. Supporting Evidence: PMID:10811803 In LAT-deficient mutant Jurkat cells, TCR engagement fails to induce ERK activation, Ca(2+) flux, and activation of AP-1 and NF-AT. |
| GO:0050852 T cell receptor signaling pathway | IDA PMID:11368773 Mapping the Zap-70 phosphorylation sites on LAT (linker for ... | ACCEPT | Summary: LAT phosphorylation by ZAP70 is necessary and sufficient to recruit and activate TCR signaling proteins. Reason: Core process; LAT is the central scaffold of proximal TCR signaling. Supporting Evidence: PMID:11368773 we reconstituted the LAT signalling pathway by demonstrating that a direct tyrosine phosphorylation of LAT with activated protein-tyrosine kinase Zap70 is necessary and sufficient for the association and activation of signalling proteins. PMID:11368773 we demonstrate that Tyr(191) and Tyr(171) are required for T-cell activation and Tyr(132) is required for the activation of PLCgamma1 and Ras signalling pathways. |
| GO:0050852 T cell receptor signaling pathway | IDA PMID:25907557 The Us3 Protein of Herpes Simplex Virus 1 Inhibits T Cell Si... | ACCEPT | Summary: HSV-1 Us3 inhibits TCR signaling by limiting LAT activation; LAT provides docking sites for PLCG1, GRB2 and VAV1. Reason: Core process; supported by this and many other studies. Supporting Evidence: PMID:25907557 provides docking sites for downstream signaling molecules such as phospholipase C Ξ³1 (PLCΞ³1), growth factor receptor-bound protein 2 (Grb2), and Vav1 |
| GO:0050863 regulation of T cell activation | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: IBA regulation of T cell activation. Reason: LAT can both promote and, via Y136-dependent signals, restrain T cell activation, but the term is downstream of its core TCR signaling role. Supporting Evidence: PMID:16002666 Mice with mutations of distinct LAT tyrosine residues (LatY136F and Lat3YF) develop lymphoproliferative disorders involving TCR alphabeta or gammadelta T cells that trigger symptoms resembling allergic inflammation. |
| GO:0050863 regulation of T cell activation | IMP PMID:12646565 Synergistic assembly of linker for activation of T cells sig... | KEEP AS NON CORE | Summary: LAT docking-site mutations affect T cell activation. Reason: Correct but downstream of the core TCR signaling function. Supporting Evidence: PMID:12646565 We found that the phospholipase C gamma docking site of LAT and different Grb2/Gads docking sites function in an interdependent fashion and synergize to accumulate LAT, Grb2, and phospholipase C gamma in TCR signaling assemblies. |
| GO:0140693 molecular condensate scaffold activity | IDA PMID:27056844 Phase separation of signaling molecules promotes T cell rece... | NEW | Summary: Reconstitution on supported bilayers shows phosphorylated LAT with Grb2/Sos1 (and Gads/SLP-76/Nck) forms liquid-like phase-separated clusters that promote TCR signaling outputs. Reason: Multivalent phospho-LAT is the membrane scaffold that nucleates signaling condensates; condensate partners SOS1 and NCK1 already carry GO:0140693 by IDA, so LAT (the scaffold itself) is a consistent addition. Supporting Evidence: PMID:27056844 When TCR phosphorylation was triggered, downstream signaling proteins spontaneously separated into liquid-like clusters that promoted signaling outputs both in vitro and in human Jurkat T cells. PMID:27056844 These results show that pLAT microclusters are liquid-like, phase-separated structures (17, 18) on membranes. PMID:27056844 Together, our data indicate that LAT cluster formation is driven by dynamically rearranging, multivalent protein-protein interactions. |
| GO:0038095 Fc-epsilon receptor signaling pathway | IMP PMID:10843385 LAT is essential for Fc(epsilon)RI-mediated mast cell activa... | NEW | Summary: LAT-deficient mast cells fail to propagate FcepsilonRI signals (SLP-76/PLCgamma phosphorylation, calcium, MAPK, degranulation). Reason: LAT acts as the same phosphotyrosine scaffold in the FcepsilonRI pathway, downstream of Syk, and is therefore a participant (not just a requirement); other pathway signaling components (SYK, PLCG1, VAV1) carry this term. Supporting Evidence: PMID:10843385 LAT-deficient BMMCs also exhibited profound defects in activation of MAPK, degranulation, and cytokine production after Fc(epsilon)RI cross-linking. PMID:10843385 These results show that LAT plays a critical role in Fc(epsilon)RI-mediated signaling in mast cells. |
| GO:0038065 collagen-activated signaling pathway | IMP PMID:10567557 LAT is required for tyrosine phosphorylation of phospholipas... | NEW | Summary: LAT is phosphorylated downstream of Syk after GPVI engagement by collagen/CRP and is required for PLCgamma2 phosphorylation and downstream platelet responses. Reason: LAT acts as a scaffold in the platelet GPVI (collagen receptor) pathway; GP6 itself carries this term. Kept non-core relative to TCR signaling. Supporting Evidence: PMID:10567557 LAT is tyrosine phosphorylated in human platelets heavily in response to collagen, collagen-related peptide (CRP), and FcgammaRIIA cross-linking but only weakly in response to the G-protein-receptor-coupled agonist thrombin. PMID:10567557 they establish a major role for LAT in the phosphorylation and activation of PLCgamma2, leading to downstream responses such as alpha-granule secretion and activation of integrin alpha(IIb)beta(3). |
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Download this section (compressed HTML)Q: Should the LAT-dependent inside-out activation of beta1 integrins after TCR engagement be captured as positive regulation of integrin activation on LAT, or only on downstream effectors (e.g. ADAP/SKAP, RAP1)?
Q: Is the mouse Lat 'COP9 signalosome' annotation (UniProt IDA, PMID:22561606) a term-selection error for 'TCR signalosome', and should it be corrected at source?
Q: Does LAT Y136 (mouse; Y132 human) phosphorylation-dependent negative feedback, revealed by LatY136F lymphoproliferation, warrant a negative regulation term, or is it best viewed as a consequence of loss of the PLCG1 docking site?
Q: A large LAT pool resides on intracellular vesicles that cycle through the Golgi/TGN (Rab6/syntaxin-16 retrograde, VAMP7/GMAP210 anterograde) and is recruited to the immunological synapse after surface LAT is phosphorylated. Should LAT carry a cellular component annotation for this compartment (e.g. intracellular vesicle or trans-Golgi network), and does vesicular LAT itself act as a signaling scaffold or mainly as a delivery reservoir for the plasma membrane pool?
Q: Is the reported DNA-PKcs phosphorylation of LAT S224/S241 (currently a single 2025 bioRxiv preprint) reproducible in peer-reviewed work, and which isoform numbering do these residues follow?
Experiment: In LAT-deficient human T cells, express LAT variants restricted to the plasma membrane or retained in the vesicular pool (e.g. by disrupting Rab6- or VAMP7-dependent traffic) and compare microcluster phosphorylation, PLCG1 recruitment and calcium/ERK output at the synapse.
Hypothesis: Vesicular LAT contributes signaling capacity at the synapse beyond replenishing surface LAT.
Experiment: Reconstitute human LAT condensates with PLCG1, GRB2-SOS1 and GRAP2-LCP2 in LAT-deficient human T cells expressing valency mutants, measuring condensate formation and Ras/calcium output by live imaging, to test whether condensate scaffolding is separable from simple adaptor docking.
Hypothesis: Condensate formation by multivalent phospho-LAT contributes to TCR signal amplification beyond simple effector docking.
Experiment: Profile IMD52 patient LAT variants for membrane targeting, phosphorylation and effector docking to determine which scaffold functions are lost in human disease.
Hypothesis: IMD52 variants differ in which LAT scaffold functions they abolish.
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