PTK2 (human, Q05397) 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/ (abstract-only for many; see
full_text_available: in each file), the Reactome cache, QuickGO and
gocams/index.tsv. No *-deep-research-*.md file was created.

Identity and architecture

• Focal adhesion kinase (FAK1), 1052 aa. FERM - kinase - proline-rich regions - FAT
  (focal adhesion targeting) domain. Isoform 6 (FRNK) is the C-terminal non-catalytic
  fragment that inhibits FAK signalling (UniProt).
• Catalytic activity: EC 2.7.10.2, L-tyrosyl-[protein] + ATP (UniProt; RHEA:10596).

Core molecular function: tyrosine kinase at integrin adhesions

• Autophosphorylation at Tyr397 is the activating switch and creates the Src docking
  site PMID:12391143.
  Note: these experiments used rat FAK isoforms PMID:12391143.
• Substrates: Cas proteins PMID:9360983;
  N-WASP PMID:14676198.
• FAK-Src dual kinase complex PMID:16919435;
  Src binding is through pTyr397-SH2 PMID:16291744,
  with an additional proline-rich/SH3 contact PMID:21266176.
• Other pTyr-SH2 partners: GRB2 PMID:7597091;
  p120RasGAP PMID:15077193.

Adhesion targeting

• Paxillin binding targets FAK to FAs PMID:7561682.
• Talin: direct FAT-talin binding; FAK recruits talin to nascent adhesions
  PMID:22270917;
  PMID:22270917.
• Integrins: PMID:26763945;
  PMID:27178753.
• Integrin dependence of FAK phosphorylation, even downstream of GPCRs
  PMID:9636140.

Processes

• Migration via GEF/GAP control of Rho GTPases PMID:19525103.
• Survival: PI3K/Akt PMID:15166238; anoikis suppression PMID:22402981.
• Nuclear scaffold for p53 degradation PMID:18206965;
  direct p53 binding PMID:15855171.
• Development (review): PMID:20552554.

Premetazoan evidence (ancestral vs animal-specific)

• Canonical FAK is holozoan, not animal-specific: PMID:20479219;
  PMID:20479219.
• Choanoflagellates lost it (with integrins and the IPP complex), retaining only a FAK-related kinase domain:
  PMID:20479219;
  PMID:20479219.
• Apusozoan Amastigomonas has most of the adhesome but not FAK or c-Src
  PMID:20479219.
  The authors' preferred scenario is a holozoan origin of the canonical machinery, with the
  alternative that FAK and c-Src were lost in apusozoans.
• Capsaspora integrin adhesion is functional, but FAK was not examined (abstract only):
  PMID:32857975;
  PMID:32857975.
• Interpretation:
• Ancestral, inferred from domain conservation only: the FAK domain set (FERM, kinase, FAT) and so,
  plausibly, kinase signalling at integrin adhesions. There is no functional FAK data from any
  non-animal.
• Animal-specific on current evidence: all developmental roles (placenta, heart, vasculature,
  neurons), growth-factor/GPCR/netrin/Eph receptor crosstalk, immune contexts, nuclear p53 regulation,
  and specialised locations such as ciliary basal bodies.
• This matches the TLN1/VCL reviews, where the integrin-talin-vinculin linkage is treated as ancestral
  (sponge biochemistry; Capsaspora filopodia), and the CSK review on Src-family regulation.

GO-CAM

gocams/index.tsv has PTK2 in two models, both with GO:0004715 non-membrane spanning protein
tyrosine kinase activity:
- 682fbcd000002551 (FAISL): part of GO:0051894 positive regulation of focal adhesion assembly.
- 689e7a5d00003515 (Ephrin-A1/EPHA2 negative regulation of cell adhesion mediated by integrin):
part of GO:0033634 positive regulation of cell-cell adhesion mediated by integrin, in focal adhesion.
The model gives FAK a positive role that EphA2/SHP2 suppresses. That is why the GOA row
"negative regulation of cell adhesion mediated by integrin" on FAK was marked over-annotated.
The cell-cell restriction does not fit the matrix-adhesion assays, so the positive row was
modified to GO:0033630.

Annotation decisions (summary)

• 75 generic protein-binding rows: 66 removed under the repository policy. 9 modified where the
  binding mode is defined: SH2 domain binding (SRC pY397, GRB2 pY925, Src SH3-SH2 peptide), SH3
  domain binding (Src SH3 NMR), p53 binding (x2), integrin binding (ITGB4), PH domain binding
  (Etk/BMX), talin binding.
• Protein tyrosine phosphatase activity (IMP, PMID:9360983) was modified to tyrosine kinase activity.
  The paper shows FAK phosphorylating Cas, and FAK has no phosphatase domain.
• UNDECIDED: actin binding (PMID:16803572, abstract silent on FAK); JUN kinase binding (PMID:10925297,
  abstract describes Jak2, possible JAK/JNK mix-up); two IL-34/macrophage IGI rows (PMID:26754294,
  abstract silent on FAK); molecular function activator activity (PMID:12467573, structure paper).
• NEW: peptidyl-tyrosine autophosphorylation (GO:0038083). FAK itself catalyses the Tyr397 step
  (Reactome R-HSA-354073).