GRAP2 (GADS) review notes

Identity and architecture

• Human GRAP2, UniProt O75791; aliases GADS, GrpL, Grf40, Mona, GRID. GRB2 family (PANTHER PTHR46037).
  SH3 (1-56), SH2 (58-149), Gln/Pro-rich linker (~143-244), C-terminal SH3 (271-330).
• Hematopoietic-restricted: PMID:9878555.
• Independent clonings: Gads from a phospho-SHC screen PMID:9872323, Mona from a phospho-Fms screen PMID:9857184, GrpL PMID:10209041, Grf40 PMID:10224278.

Core mechanism: LAT-GADS-SLP-76 bridge

• C-SH3 binds SLP-76 RxxK motif with high affinity, constitutively:
  PMID:10021361;
  PMID:12176364;
  PMID:17235283.
• SH2 binds phospho-LAT: PMID:10811803;
  PMID:15029250.
  Numbering: these are short-isoform LAT numbers; in canonical LAT O43561-1 they are Y200/Y220 (and Y132 -> Y161, Y226 -> Y255), per the LAT review.
• Knockouts: PMID:11239162;
  human Jurkat KO PMID:25452106.
• Mast cells: PMID:18664516.
• Platelets: partial/redundant role PMID:18826392; PMID:31948362.
• Review: PMID:31402911.
• Other partners: HPK1 via C-SH3 PMID:11313918; CD6 pY629 via SH2 PMID:28289074; ITK phosphorylates Gads Y45 PMID:33931484.
• Does not bind SOS: PMID:9872323; PMID:10209041.

Curation decisions (summary)

• 97 GOA rows: 52 protein binding IPI rows. Mechanistic SLP-76 rows (PMID:17235283, 17010654, 20534575) -> MODIFY to
  signaling adaptor activity (GO:0035591), consistent with LCP2. Phosphopeptide/SH2 assays (LAX1, ERBB2 array, KIT/GAB1 FP) ->
  MODIFY to phosphotyrosine residue binding (GO:0001784). All other screen-derived rows removed as uninformative.
• Nucleus/nucleoplasm/endosome kept as non-core (overexpression/HPA observations, no function). Ras signal transduction and
  cell-cell signaling (TAS, cloning paper) marked over-annotated.
• NEW: T cell receptor signaling pathway (GO:0050852), Fc-epsilon receptor signaling pathway (GO:0038095), part_of TCR
  signalosome (GO:0036398). Comparator: LAT and LCP2 (same-complex adaptors) carry all three; GADS does part of the work
  (physical bridging), so the participation test is met.
• GPVI/CLEC-2 and M-CSF receptor roles left as suggested questions (partial/redundant phenotypes or overexpression only).

Deep research integration (falcon)

Report: GRAP2-deep-research-falcon.md (Edison/Falcon, completed 2026-10-03 after ~21 min). It arrived after the
annotation review was drafted; every substantive claim was checked against primary literature before use.

Adopted (traced to primary papers, cached and quoted in the review):
- Human HuT78 GADS knockdown: reduced SLP-76/PLCG1 recruitment to LAT, calcium and IL-2/IFN-g, with preserved SLP-76/PLCG1
phosphorylation and adhesion PMID:25636200.
Added to the NEW TCR signaling row and core function 1.
- Full-length GADS-SLP-76 Kd 9 nM and the circular LAT-GADS-SLP-76-PLCG1 quaternary complex
PMID:30510001. Added to core function 1.
- Jurkat GRB2-family knockouts / AP-MS: PMID:37006259;
GADS loss remodels the SLP76 interactome but minimally affects proximal events. Added to core function 1 and a suggested question.
- FLT3 pY955/pY969 binding (PMID:26895103): recorded as a suggested question only (overexpression/xenograft); explains the
Reactome "Active FLT3 binds to GRAP2" cytosol row.

Not adopted / limitations:
- CD28 binding (Ellis et al. 2000, J Immunol, DOI 10.4049/jimmunol.164.11.5805): no PMID resolved for the DOI via the ID
converter; not cited. It is consistent with the Reactome "Gads binds CD28" row (cytosol, accepted) and with PMID:31402911.
- HPK1-mediated phosphorylation of GADS T262: not traced to a cached primary paper; PMID:25452106 reports the T262 site by MS
only. Not used.
- Microcluster dynamics drawn from a 2000 thesis (liu2000) cited by the report: not used.

Report errors / caveats:
- LAT Y171/Y191 given in short-isoform numbering without the canonical O43561-1 equivalents (Y200/Y220).
- Mast-cell phenotype attributed to the Yablonski review; the primary Gads-/- mast cell paper is PMID:18664516 (used instead).
- No outright factual errors found in the claims checked.