PLCG1 (human, P19174) review notes
2026-09-30 initial review
Context: reviewed as the PLC-gamma output branch of the FGFR signaling module
(modules/fgfr_signaling.yaml, annoton plcg1_phospholipase, GO:0004435). Review kept
gene-centric; PLCG1 is a general RTK / immune-receptor effector.
Core biology (with provenance)
Decisions
- 73
protein binding IPIs: MODIFY -> GO:0001784 phosphotyrosine residue binding where the
cited abstract shows pTyr/SH2-dependent binding (PMIDs 1656221, 1396585, 7993895, 8657103,
10811803, 8384556, 24728074, 15641795, 8321198); all others REMOVE as uninformative
(not disputing the interactions).
- GO:0004629 (C-type glycerophospholipase) -> MODIFY to GO:0004435 (assays measure IP3 from PIP2).
- GO:0008180 COP9 signalosome (IDA, PMID:22561606): REMOVE. The Tespa1 abstract speaks of the
"TCR signalosome"; PLCG1 is not a CSN subunit. Looks like a lexical mis-mapping.
PMID:22561606
- GO:0140324 lysophospholipase C (ISS from rat): MARK_AS_OVER_ANNOTATED, no human evidence.
- GO:2000353 positive regulation of endothelial apoptosis (miRNA study, abstract-only):
MARK_AS_OVER_ANNOTATED. GO:0002862 (Reactome FCGR3A-IL10): MARK_AS_OVER_ANNOTATED.
- GO:0005085 GEF (dynamin, rat ISS): KEEP_AS_NON_CORE; flagged as question.
- PMID:2550068 (platelet PLC purification, abstract-only) supports PLC activity / cytosol /
PM; "PLC-II" is a recorded synonym of PLCG1. Deferred to curator (ACCEPT).
- PMID:15702972 (PLC-eta cloning) cytoplasm IDA: ACCEPT, full text not available; location
consistent with all other evidence.
- NEW: GO:0008543 FGFR signaling pathway. Participation: PLCG1 performs the PIP2 hydrolysis
step. Comparator: PLCG1 carries GO:0007173 (EGFR) for the same role; FRS2 carries
GO:0008543 (QuickGO: IGI PMID:9660748, IBA); GRB2 does not. No PLCG1 ortholog (human
P19174, mouse Q62077, rat P10686) carries GO:0008543 (QuickGO query 2026-09-30).
Module relevance
- GO:0004435 is well supported (IBA from PTN007434641, IDA, IMP-derived via MODIFY).
- FGFR pY766 recruitment directly supported by cached PMID:1379697, PMID:1656221,
PMID:8321198, PMID:23063561. FGFR-driven mitogenesis does not require the branch
(title of PMID:1379697), consistent with the module marking it optional.
Notes from the ADAPTIVE_IMMUNITY review (merged)
A second, independent review of PLCG1 was written on branch claude/immune-system-pathways-bm50oy (ADAPTIVE_IMMUNITY project) while the FGFR-module review above was merged to main. The two agreed on 190 of 231 shared rows. On merge, main's review was kept as the base, including its REMOVE of 39 bare protein binding rows (where this branch had MODIFY to phosphotyrosine/proline-rich/small GTPase binding), its MARK_AS_OVER_ANNOTATED for lysophospholipase C (GO:0140324) and endothelial apoptosis (GO:2000353), and its IGI NEW row for FGFR signaling. Ported from this branch: NEW rows for PDGFR (GO:0048008, IDA PMID:1396585) and VEGFR (GO:0048010, IDA PMID:11387210) signaling, which answer main's open question on core receptor contexts and are added to the phosphotyrosine-binding core function; extra support for the FGFR NEW row (PMID:23063561); references PMID:11387210, PMID:31889510 and PMID:33929486; a description sentence on LAT cross-linking; four suggested questions and four experiments. This branch's falcon report is kept as PLCG1-deep-research-falcon-2.md (artifact paths updated to the -2 folder).
The original notes from that review follow.
PLCG1 review notes
Session 2026-09-30 (ADAPTIVE_IMMUNITY, TCR trunk)
Setup
just fetch-gene-pmids human PLCG1: 57/57 publications cached (many abstract-only).just deep-research-falcon human PLCG1 --fallback perplexity-lite launched in parallel. Status recorded at end of this entry.
Biology summary (with provenance)
- Core catalytic activity: PIP2 -> IP3 + DAG. PMID:37422272
- Human germline S1021F gain-of-function variant increases IP3 and Ca2+ release and causes immune dysregulation. PMID:37422272
- RTK recruitment via SH2 domains: FGFR1 pY766 PMID:1656221, PDGFRB pY1009/pY1021 PMID:1396585, EGFR pY992/pY1068 PMID:7993895; SH2-dependent translocation to plasma membrane and ruffles PMID:11331309.
- Autoinhibition release by nSH2/cSH2 coordination and Y783 phosphorylation in FGFR signalling PMID:23063561.
- TCR: PLCG1 binds phospho-LAT by SH2 PMID:10811803; ITK phosphorylates and activates it PMID:28598420. SLP-76 Y173 is needed for PLCG1 phosphorylation in T and mast cells PMID:21725281.
- EGF-induced Ca2+ rise requires PLCG1 PMID:22454520.
- SH3 domain: binds proline-rich partners (TNK1, SLP-76, Sam68, WASP); reported Rac1 GEF activity in vitro PMID:19264842. Treated as non-core.
- Lipase-independent mitogenic role in SCC cells PMID:20510673.
Framing decision
PLCG1 is broadly expressed and pleiotropic. TCR signalling is one of several core receptor contexts, alongside EGFR, FGFR and PDGFR (and VEGFR2 per Reactome). Core functions were written to reflect this rather than an adaptive-immunity-only view.
Annotation decisions
protein binding (72 IPI rows): MODIFY -> GO:0001784 phosphotyrosine residue binding where the evidence is SH2/pTyr recruitment (RTKs, LAT, BLNK, CD22, SYK, villin, EAT-2, CAV1 pY14, phosphopeptide arrays); MODIFY -> GO:0070064 proline-rich region binding for SH3 interactions (TNK1, SLP-76, Sam68, WASP, SH3 peptide array PMID:17474147); MODIFY -> GO:0031267 small GTPase binding for RAC1; REMOVE for co-IP/AP-MS/PLA/BioID-only hits, AKT1 (PLCG1 is the substrate), INSR (binding mechanism unresolved: SH2 vs PH-EF), SR-BII (not physiological), EEF1A2, THEMIS, GRB2, SOS1, Tespa1, FGFR2 (SH3 binding to C terminus; site nature not stated).- C-type glycerophospholipase activity -> MODIFY to GO:0004435, matching PLCG2 review.
- COP9 signalosome IDA (PMID:22561606, abstract only): the abstract describes the TCR signalosome, not CSN. UNDECIDED (cannot see full text; do not overrule).
- Lysophospholipase C (ISS from rat): UNDECIDED; no human evidence found.
- miR-30 paper (PMID:27464494, abstract only): EC proliferation KEEP_AS_NON_CORE; EC apoptosis UNDECIDED.
- Downstream phenotypes (migration, angiogenesis, EC migration, IL10/inflammatory response): KEEP_AS_NON_CORE or MARK_AS_OVER_ANNOTATED (Reactome FCGR3A-IL10 row), per necessity-vs-participation guidance.
- NEW: GO:0008543 FGFR signaling pathway (PMID:23063561) and GO:0048008 PDGFR signaling pathway (PMID:1396585). Participation test: PLCG1 is the catalytic effector that performs PIP2 hydrolysis within these pathways; comparable to its existing EGFR signaling annotation.
Validation
just validate human PLCG1: valid, no errors or warnings.
Deep research status
- The falcon deep-research job (
just deep-research-falcon human PLCG1 --fallback perplexity-lite) was still running after about 35 minutes, when this review was completed. The perplexity-lite fallback is not available here: sibling runs logged "Provider 'perplexity' not available". This review therefore relies on the cached publications and UniProt, not deep research. If PLCG1-deep-research-falcon.md appears later, check it against the core functions above.
- Update: the falcon run finished at 13:59 UTC, after the review, and wrote
PLCG1-deep-research-falcon.md. A quick scan agrees with the review: it describes PIP2 hydrolysis downstream of EGFR (pTyr992), FGFR, PDGFR and the TCR; the SH3 domain binding proline-rich partners; the dynamin-1 GEF activity as secondary; and a nuclear PLCG1 fragment. It says nothing about COP9 signalosome or lysophospholipase C, so those rows stay UNDECIDED.
Deep research integration (falcon)
Session 2026-10-01. Report: PLCG1-deep-research-falcon.md (Edison/falcon; 28 citation tags, but only 6 distinct sources: Hajicek 2019 eLife, Chen & Simons 2021 Sci Signal review, Kanemaru & Nakamura 2023 Biomolecules review, Zeng 2020 bioRxiv preprint, and two unpublished theses, Duarte 2023 and Nanna 2026). No PMIDs given; DOIs resolved through PubMed.
Claim classification (about 30 substantive claims)
- Confirms review (~18): PIP2 -> IP3 + DAG catalysis, Ca2+-dependence; IP3 -> ER Ca2+ release, DAG -> PKC; cytosolic/autoinhibited at rest; Y783 phosphorylation relieves autoinhibition (plus Y771, Y775, Y1253); RTK recruitment via SH2 (EGFR pY992, PDGFR pY1021, FGFR1 pY766); TCR/LAT/ITK coupling; Ca2+/calcineurin/NFAT and DAG/PKC/RasGRP/ERK arms; plasma membrane translocation; ruffles/lamellipodia/migration; SH3 binding proline-rich partners (SOS, dynamin-1, SLP-76); dynamin-1 GEF activity; Rac1 activation via SH3; EGF-induced migration; angiogenesis and T cell phenotypes as downstream (non-core) outcomes; gain-of-function cancer mutations.
- Adds something new (5): (1) structural detail of autoinhibition (regulatory array over the catalytic core; cSH2-C2 clasp displaced by pY783); (2) VEGFR2 (KDR) pY1175 docking and the PLCG1-PKC-ERK route in endothelial cells; (3) LAT condensate/phase-separation scaffolding and CD45 protection; (4) focal adhesion localization with GIT1/beta-PIX/FAK; (5) nuclear ~120 kDa PLCG1 fragment.
- Conflicts with review (1): SH3 domain binds AKT (review REMOVEd the AKT1 protein-binding row, reading PMID:16525023 as AKT binding and phosphorylating PLCG1).
- Not relevant or unsupported (~6): domain boundary table; cell-cycle regulator induction (Cdk4, cyclin D1, p27 export); erythropoiesis; PKC feedback on EGFR T654; DLL4/Notch tip/stalk selection; JAK2/GRB2/FAK SH2 partners. These come from reviews/theses or describe downstream pleiotropy.
Claims adopted (and where)
- Autoinhibition mechanism ->
description; core_functions[0].supported_by with two verbatim quotes from PMID:31889510 (Hajicek 2019, full text cached via just fetch-pmid).
- VEGFR2 ->
description; NEW existing_annotations row GO:0048010 vascular endothelial growth factor receptor signaling pathway (IDA, PMID:11387210, Takahashi 2001 EMBO J, full text cached); GO:0048010 added to core_functions[0].directly_involved_in; KDR added to the SH2 core function with PMID:11387210 support. NEW bar: PLCG1 performs the PIP2 hydrolysis step (catalytic effector, not substrate). Comparator check (QuickGO): PRKCB, PRKD1, PRKD2, PTK2, SRC, FYN, VAV1 carry GO:0048010 in human, so effectors do get the term. The review already listed VEGFR2 as a core receptor context (PDGFR NEW row reason, core function text) without a term. Caveat noted: the experiments used human KDR in mouse/bovine endothelial cells and a pan-PLC-gamma antibody.
- LAT condensate scaffolding ->
description; core_functions[1].supported_by (PMID:33929486, the peer-reviewed J Cell Biol 2021 version of the preprint the report cites; plus a verbatim quote from the report). No new MF annotation; raised as a question instead.
- References added: the falcon report (reference_review LOW_QUALITY: secondary, theses, no PMIDs), PMID:11387210, PMID:31889510, PMID:33929486.
Claims not acted on (and why)
- Focal adhesion and nuclear fragment localizations: only supported by reviews (Chen & Simons; Kanemaru & Nakamura) in the report; no primary paper checked. Raised as a question; no NEW CC terms.
- SH3-AKT binding: from a thesis (Duarte 2023) only; conflicts with the review's reading of PMID:16525023. Raised as a question; AKT1 row left as is.
- Erythropoiesis, cell-cycle regulators, Notch tip/stalk, PKC-EGFR feedback: downstream or pleiotropic, review-sourced only.
UNDECIDED rows
- The report does not mention COP9 signalosome (GO:0008180), lysophospholipase C (GO:0140324) or endothelial apoptosis, so it offers no primary leads for them. COP9 and lysophospholipase C stay UNDECIDED (the Tespa1 paper PMID:22561606 and the rat donor evidence are still not available as full text).
- GO:2000353 positive regulation of endothelial cell apoptotic process (PMID:27464494): changed UNDECIDED -> KEEP_AS_NON_CORE. This was not prompted by the report: the earlier reason said the direction could not be read from the abstract, but the paper's title ("MiR-30s Family Inhibit the Proliferation and Apoptosis ... Through Targeting ... PLCG1") states it, which matches the curator's positive-regulation term. Now handled the same way as the sibling proliferation row from the same paper.
Report errors / weaknesses detected
- The domain table is labelled "human PLCgamma1", but the structural source (Hajicek 2019) solved rat PLC-gamma1 (P10686). The report never says the structure is human, but it presents the structural data as human.
- Hajicek 2019 is listed under "Recent Developments (2023-2024 Sources)".
- Zeng et al. is cited as a 2020 bioRxiv preprint; it was published as J Cell Biol 2021 (PMID:33929486). Minor detail: the paper says nSH2 binds LAT Y132; the report's "Tyr132 and Tyr171" cross-linking was not checked.
- Two of the six sources are unpublished theses ("Unknown journal"); no PMIDs anywhere. No hallucinated PMIDs (none given); all four DOIs resolved to real papers.
Validation
just validate human PLCG1: valid, all validations passed.