CSK (human, P41240) 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/, the Reactome cache, QuickGO
and the PANTHER PAINT files. No *-deep-research-*.md file was created.

Identity and domain architecture

• C-terminal Src kinase, 450 aa, SH3 - SH2 - tyrosine kinase domain; no
  N-terminal fatty acylation signal, no activation-loop autophosphorylation
  tyrosine PMID:1945408.
• Originally cloned as "cyl" from K562 cells PMID:1945408.

Core molecular function: inhibitory C-terminal tail phosphorylation of Src-family kinases

• Human CSK phosphorylates Lck Tyr-505 and suppresses Lck activity
  [PMID:1639064 "Here we characterize a human cytosolic 50 kDa protein tyrosine kinase, p50csk, which specifically phosphorylates Tyr-505 of p56lck and a synthetic peptide containing this site"; PMID:1639064 "Phosphorylation of Tyr-505 suppressed the catalytic activity of p56lck"].
• Inactivates Yes PMID:9281320.
• Autophosphorylation and activity on artificial substrates (rat Csk in E. coli)
  PMID:7683130.
• Substrate specificity is set by a docking interface between the two kinase
  domains, not by the conventional peptide-binding site
  PMID:18614016.
• SH3 and SH2 domains are needed for full activity but not for Src recognition
  PMID:15683240.
• Reported non-SFK substrates: CD45 (PMID:7507203), PD-1 (Reactome R-HSA-389762),
  bacterial EPIYA effectors (PMID:24902122). These are minor/contextual.

Membrane recruitment via SH2 binding to phosphotyrosine adaptors

• CSK is mainly cytosolic and is brought to its membrane-anchored SFK substrates
  by SH2-mediated binding to tyrosine-phosphorylated adaptors and receptors.
• PAG/Cbp: PMID:10790433.
• IGF-1R/IR: PMID:10026153.
• H. pylori CagA: PMID:12446738.
• SCIMP: PMID:21930792.
• H. ducreyi LspA1: PMID:24902122.
• PKA phosphorylates and activates CSK in T-cell lipid rafts
  PMID:17911601.

SH3 domain: PEP/PTPN22 binding and homodimerization

• PMID:8890164.
• PMID:19888460.

Physiological processes (animal context)

• Negative regulation of antigen-receptor signalling in T cells
  PMID:8890164.
• Phagocytosis: CSK activity inhibits SFK-dependent Fc-gamma-R phagocytosis
  PMID:24902122.
• Golgi export of Lyn PMID:20605918.
• Many of the IEA (Ensembl Compara) process rows derive from rat Csk experiments
  (QuickGO, P32577): bone resorption, IL-6 and proliferation from adenoviral Csk
  overexpression in arthritic joints (PMID:10411542); LDL clearance and phagocytosis
  from Csk-transfected J774 macrophages (PMID:10884975); Fc-epsilon-R and ERK from
  PMID:9325302; oligodendrocyte differentiation (IEP, PMID:15504915); adherens
  junction organization (IEP, PMID:15389520, rat seminiferous epithelium). These
  rat papers were identified from QuickGO and PubMed esummary titles only; they
  were not read.

IBA rows

• GO:0004715 from PTN001231168 (Bilateria node, PTHR24418, seeded by fly Csk
  FBgn0262081). Sound.
• GO:0034332 adherens junction organization and GO:0060368 regulation of Fc
  receptor mediated stimulatory signaling pathway from PTN002815304 (taxon
  Euteleostomi, 117571), both seeded only by rat Csk (RGD:1308800). The adherens
  junction seed is an IEP annotation (expression in rat testis), which is weak
  for a process claim. Kept as non-core.
• GO:0005886 plasma membrane IBA: broad SFK/CSK node; fine.

GO-CAM

• No entry for CSK / P41240 in gocams/index.tsv, so no GO-CAM role to reconcile.

Premetazoan context (ancestral vs animal-specific)

• Phosphotyrosine signalling machinery predates animals
  PMID:18273011.
• Choanoflagellate M. ovata has a functional Csk ortholog that phosphorylates Src
  tail tyrosines [PMID:16873552 "we show that the src gene family and its C-terminal Src kinase (Csk)-mediated regulatory system already were established in the unicellular M. ovata"; PMID:16873552 "These observations demonstrate that MoCsk and EfCsk are functional orthologs of Csk and that both Src and Csk functions are, at least partially, complementary between E. fluviatilis , M. ovata , and vertebrates."].
  But choanoflagellate Src is only weakly inhibited by it.
• M. brevicollis Csk: active, phosphorylates the MbSrc1 tail, but the phosphorylation
  does not inhibit MbSrc1 PMID:18390552.
• Contrary result (abstract only read): inhibition of Src by Csk demonstrated for
  Capsaspora and M. brevicollis proteins in yeast/in vitro assays
  PMID:28939764.
• Summary: CSK's catalytic activity (tyrosine kinase that phosphorylates the
  Src C-terminal tail) is ancestral to Holozoa, verified biochemically in two
  choanoflagellates and (per an abstract) Capsaspora and Corallochytrium. Whether
  that phosphorylation was already inhibitory before animals is disputed
  (PMID:16873552, PMID:18390552 vs PMID:28939764). The adaptor-mediated
  recruitment system (PAG/Cbp, SCIMP, PTPN22/PEP), and all the process rows
  (T-cell receptor, Fc receptor, bone resorption, adherens junctions, phagocytosis
  by immune cells) are animal-specific contexts. I did not find evidence for
  choanoflagellate or Capsaspora orthologs of PAG/Cbp in the papers read, so
  that point is left open.

Action summary rationale

• protein binding (GO:0005515) rows: REMOVE unless the paper supports a specific
  MF; MODIFY to GO:0001784 phosphotyrosine residue binding for SH2-mediated
  binding to phospho-IGF1R/IR (PMID:10026153), phospho-CagA (PMID:12446738),
  phospho-SCIMP (PMID:21930792), phospho-LspA1 (PMID:24902122); MODIFY TAS PEP row
  (PMID:8890164) to proline-rich region binding / protein phosphatase binding.