NEDD9 (HEF1 / CAS-L, Q14511) - curation notes

Deep research status

• Falcon deep research first launched with --fallback perplexity-lite (600 s timeout; fallback unavailable),
  then relaunched with --timeout 2400. See "Deep research outcome" at the end of this file.
• Review written from cached publications, UniProt Q14511, and two papers added to the cache during this review
  (PMID:16184168 HEF1 activates Aurora A; PMID:17174122 Chat-H/CasL in T-cell trafficking).

Summary of function

• Cas-family docking protein: SH3 domain binds FAK
  PMID:8668148.
• Family: PMID:9584194.
• Integrin-induced tyrosine phosphorylation by FAK then Src-family kinases
  [PMID:9360983 "We show here that p130(Cas) and Cas-L are FAK substrates"; "the phosphorylated YDYVHL sequence is a binding site for Src family protein-tyrosine kinases"].
• Localization: PMID:9584194.
• Migration: PMID:24574519;
  NEDD9 scaffolds a NEDD9-AURKA-CTTN complex PMID:24574519.
• Lymphocytes: Abl-dependent HEF1 phosphorylation for chemokine-induced migration and Rap1 activation PMID:22810897.
• Mitosis: relocalizes to spindle, regulates RhoA via ECT2 PMID:16394104.
• Aurora A activation: PMID:16184168;
  in vitro: PMID:16184168;
  PMID:16184168.

Cilium disassembly (non-dominant function)

• PMID:17604723.
• NEDD9's contribution is the activator step (kinase activator activity toward AURKA), which I proposed as a NEW
  MF annotation (GO:0043539 protein serine/threonine kinase activator activity, IDA PMID:16184168). No NEW process
  terms were proposed.

Key curation decisions

• protein binding IPIs: REMOVE for most (incl. high-throughput Y2H/AP-MS, SMAD3/ITCH, ECT2, BCAR3, MICAL1,
  PLK1 docking). MODIFY where the paper supports something more specific: FYN and ABL1 -> protein tyrosine kinase
  binding (GO:1990782); PTPN11/SHP-2 -> protein phosphatase binding (GO:0019903); NEDD9-AURKA-CTTN scaffold ->
  protein-macromolecule adaptor activity (GO:0030674).
• negative regulation of cell migration ISS: UNDECIDED (conflicts with strong positive evidence; source not inspected).
• actin filament bundle assembly NAS PMID:11827972: MARK_AS_OVER_ANNOTATED (paper links CasL to vimentin
  intermediate filaments via MICAL, not to actin bundling).
• Mouse-derived ISS process terms (learning/memory, dendritic spine maintenance, osteoclast differentiation,
  lymphocyte homing/chemotaxis, immunological synapse): KEEP_AS_NON_CORE.
• Nuclear, Golgi, spindle, spindle pole: KEEP_AS_NON_CORE. Focal adhesion, cytoplasm, ciliary basal body: ACCEPT.

HPA cilium atlas vs module role

• HPA v25 (member_evidence.md): no cilium, basal-body or centrosome call; main locations Cytosol; Nucleoplasm.
  The GOA GO_REF:0000052 rows (cytosol, nucleoplasm) were accepted / kept as non-core.
• PMID:41005307 (Hansen et al. 2025, HPA cilium atlas) does not mention NEDD9/HEF1 in its cached text.
• Module (stage 7): NEDD9 as an Aurora A activator at the basal body (with CIMAP3), function "kinase activator".
• Comparison: the HPA atlas does not detect NEDD9 at the basal body; the basal-body localization rests on
  PMID:17604723 (IDA) and on cell-type/stimulus-dependent recruitment (serum-induced resorption). The absence of an
  HPA basal-body call is not a contradiction (NEDD9's basal-body pool is likely transient and small relative to its
  focal-adhesion/cytosolic pool), but it means the module role is supported by a single lab's work rather than by
  independent localization data.
• Module caution: NEDD9 is primarily a focal-adhesion Cas scaffold; its ciliary role is real but non-dominant. The
  module's "kinase activator" function maps to GO:0043539 (proposed here as NEW).

Deep research outcome

• Falcon succeeded on the second run (--timeout 2400): NEDD9-deep-research-falcon.md. Its conclusion agrees
  with this review: NEDD9 is primarily a phosphorylation-regulated Cas-family adaptor/scaffold for integrin and
  receptor signalling at focal adhesions, with basal-body AURKA-HDAC6 cilium resorption, centrosomal AURKA
  regulation at mitotic entry, and T-cell signalling as experimentally supported additional, context-dependent
  functions [file:human/NEDD9/NEDD9-deep-research-falcon.md "assign human NEDD9 primarily as a phosphorylation-regulated CAS-family intracellular adaptor/scaffold for integrin- and receptor-initiated signaling at focal adhesions"].