FRS2 (Q8WU20) curation notes

Identity

• FRS2 / FRS2alpha / SNT-1; 508 aa; N-myristoyl Gly2, IRS-type PTB domain (13-115), long disordered
  C-terminal tail with FGFR-phosphorylated tyrosines (Y196, Y306, Y349, Y392, Y436, Y471 by similarity
  to mouse Q8C180) (UniProt FRS2-uniprot.txt). Paralog FRS3 (FRS2beta/SNT-2, O43559); PANTHER
  PTHR21258:SF40 (DOK-related docking proteins).

Core biology (with provenance)

• Discovery as lipid-anchored docking protein: PMID:9182757; myristoylation needed PMID:9182757.
• Direct PTB-domain binding to FGFR1 juxtamembrane (non-pY motif): PMID:9660748; constitutive for FGFR1 but
  activation-dependent for TrkA PMID:10629055; NMR structural basis PMID:11090629.
• Effector recruitment: SHP2 via N-SH2 PMID:9632781; GRB2
  direct and indirect PMID:9632781; PI3K via GRB2-GAB1 PMID:11353842.
• Other RTKs: TrkA/Trk family (PTB binds NPXpY, competes with SHC) PMID:10092678, with functional rescue of NGF differentiation
  PMID:10092678; ALK PMID:17274988; EGFR in A-431 cells PMID:12974390; RET per UniProt "Binds RET (By
  similarity)" (not independently verified here - no RET paper cached).
• Negative feedback: PMID:12974390.

Localization

• Cytoplasmic face of the plasma membrane via myristoylation PMID:9182757. Reactome places FRS2 in cytosol
  for several TrkA/TrkB reactions - compartment modelling artefact, marked over-annotated.
• Adherens junction IDA from E-cadherin BioID (PMID:25468996) - high-throughput proximity; non-core.

Decisions summary

• GO:0005068 (RTK adaptor) accepted as core MF; it is the right term for FRS2 in the FGFR module and also
  covers Trk/ALK/RET/EGFR use since the term is not FGFR-specific.
• GO:0005515 protein binding rows MODIFIED to FGFR binding (FGFR1 partners), SH2 domain binding
  (Hadari 1998 SHP2 N-SH2), protein phosphatase binding (LuTHy PTPN11).
• TAS from PMID:9660748 for GPCR signaling (GO:0007186) and receptor PTP signaling (GO:0007185) removed:
  unsupported by paper; SHP2 is a non-receptor PTP. Phosphatase activator activity marked over-annotated.
• Considered NEW GO:0048011 neurotrophin TRK receptor signaling pathway (participation evidence from
  Meakin 1999 rescue). Comparator check (QuickGO 2026-09-30): SHC1 (P29353), FRS3 and mouse Frs2 carry no
  GO:0048011/GO:0038180 annotation, so not proposed; raised as a suggested question instead.