SRC (human, P12931) review notes

Automated deep research was unavailable for this gene (no deep-research provider
keys in this environment). These notes were compiled manually from the UniProt
record, the cached publications in publications/, QuickGO, the GO-CAM index and
the GOA file. No *-deep-research-*.md file was created.

Identity and regulation

• 536 aa; N-terminal myristoylated SH4/unique region, SH3, SH2, tyrosine kinase
  domain, C-terminal tail (UniProt). Catalytic activity EC 2.7.10.2 (UniProt,
  many IDA/EXP sources).
• Tail phosphorylation by CSK (Tyr530) and SH2-tail / SH3-linker clamps hold
  SRC inactive; activation-loop autophosphorylation (Tyr419) activates it
  PMID:17921256.
• Tail dephosphorylation by PTPRA uses SH2 displacement
  PMID:10698938.
• Autophosphorylation as a regulated step
  PMID:17491594.
  Proposed as NEW GO:0046777 protein autophosphorylation (comparator: LYN has
  it by IDA; LCK and FYN do not, so no convention against it).

Binding modes (basis for protein-binding MODIFYs)

• SH2 to phosphotyrosine: PYK2 Tyr402
  PMID:8849729;
  ERalpha pTyr537 PMID:14963108;
  PECAM-1 PMID:9162084;
  MVP PMID:16441665.
• SH3 to proline-rich motifs: CBL
  PMID:17094785;
  p140Cap PMID:17525734;
  integrin beta3 PMID:16115959;
  Kv1.5 PMID:8953041.
• C-terminal PDZ-binding motif: PMID:17491594;
  PMID:17936276.
  The 21 PDZ-protein rows from the fragmentomics screen (PMID:36115835) were
  modified to PDZ domain binding on this basis.

Sites of action

• Endosomes to focal adhesions on activation
  PMID:7525268.
• Focal adhesion turnover with FAK and dynamin-2
  PMID:21411625
  (basis for MODIFY of focal adhesion assembly to focal adhesion disassembly).
• Mitochondrial pool PMID:12615910.
• Integrin-beta5 signalling PMID:24036928.

GO-CAM models containing SRC (gocams/index.tsv)

All five models use SRC as an enabler of protein tyrosine kinase (or protein
kinase) activity:
- 645d887900001502 Src-ZNRF1 axis controls TLR3 trafficking: GO:0004713 ->
regulation of TLR3 signaling pathway, cytoplasm (PMID:37158982).
- 646ff70100004025 mTORC1 via OTUB1 deubiquitination of RPTOR: GO:0004713 ->
positive regulation of TORC1 signaling (PMID:35927303).
- 66c7d41500000715 CLEC12A inhibits neutrophil activation: GO:0004713 ->
negative regulation of neutrophil activation (PMID:34234773).
- 6870555700001571 laminin/dystroglycan Rac1 signalling: GO:0004713 ->
positive regulation of Rac protein signal transduction.
- 68d5ebd600001504 KISS1/KISS1R and osteoclasts: GO:0004672 -> osteoclast
differentiation, cytoplasm.
These are consistent with the core kinase function; the corresponding process
rows were kept as non-core context-specific roles.

Premetazoan evidence: ancestral versus animal-specific

• Choanoflagellates have an expanded tyrosine kinase / SH2 / PTP repertoire
  PMID:18273011.
• Src and Csk regulation exist in Monosiga ovata, but unicellular Src stays
  partly active after Csk phosphorylation
  PMID:16873552;
  PMID:16873552.
• M. brevicollis Src1 has mammalian-like domain functions, but SH2 and
  catalytic domains are not coupled, and MbCsk tail phosphorylation does not
  shut it down
  PMID:18390552;
  PMID:18390552;
  PMID:18390552.
• Disputed: a later yeast/in vitro study (abstract only read) reports Csk
  inhibition of Src in Capsaspora and M. brevicollis
  PMID:28939764.
  This is the same dispute recorded in the human CSK review
  (genes/human/CSK/); SRC is kept consistent with it: tail phosphorylation by
  Csk is ancestral, strong inhibition outside animals is disputed.
• Capsaspora phosphoproteome changes across life stages include tyrosine
  kinases (abstract only)
  PMID:27746046.
  No Src-specific substrate data were found in the cached text.

Summary:
- Ancestral (in choanoflagellates): non-receptor tyrosine kinase activity;
SH3, SH2 and kinase domain architecture with SH2 phosphopeptide and SH3
binding; C-terminal tail phosphorylation by Csk; probable activation-loop
autophosphorylation.
- Disputed: whether Csk tail phosphorylation was strongly inhibitory
before animals, and whether SH2 engagement was coupled to catalytic
regulation.
- Animal-specific on current evidence: the substrate and partner network at
focal adhesions (FAK/PYK2, p130Cas), adherens and gap junctions, PDZ scaffold
interactions, and the receptor-specific pathways (RTK, cytokine, immune,
osteoclast bone resorption, vascular permeability). No unicellular-relative
study in the cache shows Src acting at adhesion structures.

IBA nodes

• PTN002521528 (Src-family level): non-membrane spanning PTK activity,
  signaling receptor binding, cell differentiation.
• PTN002815154 (narrower node, seeded by rat/human Src): cell adhesion, EGFR
  signalling, progesterone receptor signalling, negative regulation of
  extrinsic and intrinsic apoptotic signalling. SRC itself is in the WITH/FROM
  for several of these, which reflects its own experimental grounding.
  None of these were removed; the broad differentiation/apoptosis ones are kept
  as non-core.

Decision summary (550 GOA rows plus 1 NEW)

• Protein binding (186 rows): 62 MODIFY where the cited text defines the mode
  (phosphotyrosine residue binding, proline-rich region binding, PDZ domain
  binding, one receptor tyrosine kinase binding), 124 REMOVE.
• Kinase activity rows accepted; protein kinase activity rows modified to
  protein tyrosine kinase activity.
• Over-annotations: telomerase/transcription screen rows (PMID:21531765),
  vasodilation, heart rate, intestinal epithelial cell development (regeneration
  paper), TGF-beta receptor signalling (integrin arm only), positive regulation
  of dephosphorylation, signal complex assembly, PTK activator activity,
  phospholipase activator activity, positive regulation of phosphate metabolic
  process.
• REMOVE (non-PB): signaling receptor activator activity (ISS from rat; kinase
  effect mistyped as activator).
• UNDECIDED: SH2 domain binding (PMID:8070403; partner p130Cas lacks an SH2
  domain, abstract only).