LCK (human, P06239) review notes

Context: ADAPTIVE_IMMUNITY project, T cell receptor trunk. Curation rules followed: activity
separated from pathway (LCK = non-membrane-spanning protein tyrosine kinase), generic
protein binding IPI rows replaced or removed, knockout/necessity evidence for downstream
processes treated as non-core.

Deep research

• just deep-research-falcon human LCK --fallback perplexity-lite launched in background at the
  start of the session. Falcon wrote LCK-deep-research-falcon.md (~16 min run, 50 citations),
  but the just recipe exited non-zero ("All providers failed") because its 600 s wrapper timeout
  fired and the perplexity-lite fallback is not configured in this environment. The falcon report
  is complete and consistent with this review (zinc-dependent CD4/CD8alpha binding via Cys20/Cys23,
  Y394 activating / Y505 CSK-inhibitory, coreceptor-bound vs free LCK pools, Wei et al. 2020 PNAS).
  Annotation decisions rest on the cached publications and the UniProt record.

Core biology (with provenance)

• Src-family non-receptor PTK; N-terminal myristoylation + palmitoylation anchor it to the inner
  leaflet of the plasma membrane PMID:22034844
• Coupled to CD4 and CD8 coreceptor tails; phosphorylates CD3 chains
  PMID:2470098
• Phosphorylates TCR zeta ITAMs, which then recruit ZAP70 tandem SH2 domains
  PMID:8681956
• Phosphorylates and activates ZAP70; SH2 domain binds ZAP70 pY319
  PMID:10318843; Lck-dependent ZAP70 Y315 phosphorylation PMID:16339550.
• Other direct substrates: LAT PMID:16938345, SH-PTP1/PTPN6 PMID:8114715, magicin
  PMID:16899217, PKD2 PMID:19192391, TSAd PMID:15827961.
• Regulation: CSK phosphorylates inhibitory Y505, CD45 dephosphorylates it; network reconstituted
  on membranes PMID:24463463. CD45 binds Lck [PMID:14625311, PMID:8576115]. Activation-loop Y394
  dephosphorylated by PTPN22 PMID:16461343 and DUSP22/JKAP PMID:24714587.
• Raft translocation after TCR/CD4 co-aggregation activates Fyn PMID:12732664.
• Mouse Lck knockout: thymic atrophy, block at DP stage PMID:1579166 -- necessity evidence.
• Also signals from Fc gamma RIIIA/CD16 in NK cells via zeta PMID:8478617, CD28/CTLA-4/PD-1
  tail phosphorylation (Reactome), IL-2R-linked signaling PMID:7852312.

Annotation decisions (summary)

• PTK activity rows (GO:0004713, GO:0004715): ACCEPT. Several EXP rows cite papers whose abstracts
  are about other kinases (v-Src 1978, KIT, Shp2, Gab2, vav); function is unambiguously correct so
  deferred to curator.
• GO:0004722 protein serine/threonine phosphatase activity (PMID:8506364): REMOVE. Paper maps
  Ser-42/Ser-59 phosphorylation OF Lck by MAPK/PKA/PKC; LCK has no phosphatase domain.
• 68 protein binding IPI rows: REMOVE unless paper supports an informative MF; MODIFY to
  phosphotyrosine residue binding (SH2-pY evidence: 10318843, 8798676, 7507203, 7852312) or protein
  phosphatase binding (CD45: 14625311, 8576115).
• Cytosol (Reactome TAS + IEA): KEEP_AS_NON_CORE; main site of action is cytoplasmic face of PM.
• Downstream processes (adhesion, calcium release, NKT activation, xenobiotic response, platelet
  activation, leukocyte migration, hemopoiesis): non-core or over-annotated.
• SH2 domain binding with HIV Nef (PMID:8794306): REMOVE -- the interaction is Nef proline repeat
  with Lck SH3; Nef has no SH2 domain.
• protein antigen binding (IEA, Ensembl Compara from mouse): REMOVE.
• Cannot verify from abstract: phospholipase activator activity / phospholipase binding (PMID:11606584,
  abstract only names Btk/Syk), protein kinase binding with RASA1 (PMID:8618896), CD27 signaling
  (PMID:38354704) -> UNDECIDED.

Deep research integration (falcon)

Report: LCK-deep-research-falcon.md (Edison/falcon, 2026-09-30). Built mainly on three reviews
(De Sanctis 2024 Cancers PMID:39123358; Fernandez-Aguilar 2023 Biology PMID:37759563; Zhang 2023
Front Cell Dev Biol PMID:36910149) and four primary papers. DOIs were resolved to PMIDs with NCBI
esearch; the four primary papers were cached with just fetch-pmid (all full text).

Claim tally (~32 substantive claims): ~19 confirm the review, 5 add something new, 0 conflict,
~8 not relevant to annotation or review-only/unsupported.

Claims adopted

• Kinase-domain-intrinsic ITAM selectivity (Lck vs Src domain swap) -> description + core_functions[0]
  supported_by PMID:42638732;
  new suggested question + experiment on the residues responsible.
• Free vs coreceptor-bound LCK pools -> description + CD4 receptor binding core function supported_by
  PMID:32571924 (mouse OT-I hybridoma). Confirms the existing
  suggested question on free vs bound pools.
• Human partial LCK deficiency (P440S) -> description PMID:37962568. Necessity evidence only; no new
  process annotation.
• Zinc clasp Cys20/Cys23 with CD4/CD8alpha -> report quoted as descriptive support on the IEA
  CD4 receptor binding row (no action change).
• Report and the four primary papers added to references with reference_review.

Claims not acted on

• CAR-T signaling via FYN without LCK (PMID:36696897): engineered-receptor context; reference added
  (relevance LOW), no annotation change.
• ZDHHC2/ZDHHC21 palmitoylation, Y192 ZAP70-mediated feedback on CD45 binding, PD-1/SHP-2
  dephosphorylation of Y394, LAG-3, CD5/CD2/CD44/CD146/CD160 signaling, ROS/ERK and NF-kB links:
  review-only in the report, no primary paper cited. Y192 feedback raised as a suggested question.
• Nuclear LCK pool (RAD51/BRCA1) in tumor cells: review-only; no nucleus annotation exists in GOA;
  raised as a suggested question, no NEW annotation.
• Therapeutics table (dasatinib, A-770041, etc.) and biomarker material: not relevant to GO.
• The report says nothing about the four UNDECIDED rows (phospholipase activator activity and
  phospholipase binding from PMID:11606584, protein kinase binding/RASA1 from PMID:8618896, CD27
  signaling from PMID:38354704); they remain UNDECIDED.

Conflicts

• None with the review. All annotation decisions stand.

Report errors detected

• "~90% kinase-domain sequence identity with Src" attributed to Karpouzou 2026; the paper says
  "60-90% sequence identity in their catalytic sites" across SFKs.
• Presents Lui 2023 as the "first detailed characterization" of human LCK deficiency; that paper itself
  discusses an earlier L341P LCK report. (Also: Lui et al. is J Exp Med 2024 issue, epub Nov 2023.)
• The 2026 Karpouzou paper is listed under "Recent Developments (2023-2024)" - cosmetic.
• No fabricated DOIs found: all seven DOIs resolved to the named papers.