ARHGDIB (Rho GDP-dissociation inhibitor 2; Ly-GDI; D4-GDI; RhoGDI2) — review notes

Deep research status: automated falcon (Edison) deep research failed with an
authentication error on 2026-10-24, and no other provider key was available. No
-deep-research-*.md file exists for this gene. The notes below come from the cached
publications in publications/, the UniProt record (P52566), cached Reactome entries,
and targeted web searches used only to locate PMIDs (all cited papers were then cached
and read from publications/).

Why this gene was reviewed

Flagged by rule FRR:0010 (projects/FUNCTION_REQUIREMENT_RULES.md): an IMP annotation
to GO:0003924 GTPase activity (assigned by CACAO, PMID:24554735). GO defines GTPase
activity as "Catalysis of the reaction: GTP + H2O = GDP + H+ + phosphate." ARHGDIB has
no P-loop GTPase domain; it is a Rho GDI family member (Pfam PF02115 Rho_GDI;
InterPro IPR000406; PANTHER PTHR10980:SF15).

Identity and family

• UniProt P52566, 201 aa (initiator Met removed, N-acetylthreonine at 2).
• "Belongs to the Rho GDI family" (UniProt SIMILARITY). Paralogs: ARHGDIA (RhoGDI1,
  ubiquitous) and ARHGDIG (RhoGDI3, Q99819). PMID:9113980
• Hematopoietic expression: PMID:8356058; PMID:7512369.

Molecular function: Rho GDP-dissociation inhibitor

• PMID:8356058
• PMID:7512369
• Structure with Rac2 (PDB 1DS6): PMID:10655614; mechanism
  PMID:10655614; RhoGDIs PMID:10655614
• Reactome lists ARHGDIB as a GDI for RHOA, RAC1, CDC42 and RHOG, and as binding RHOH
  (Reactome:R-HSA-9012835, R-HSA-9013147, R-HSA-9013158, R-HSA-9014456, R-HSA-9018754).

Cellular effects / processes

• Overexpression disrupts stress fibres and focal contacts PMID:8262133, consistent with inactivation of Rho proteins.
• Trophoblast migration [PMID:24554735 "Overexpression of RhoGDI2 in HTR-8/SVneo cells
  was associated with reduced RAC1-guanosine triphosphate (GTP) levels and inhibited
  cell migration."; "small interfering RNA-mediated downregulation of RhoGDI2 resulted
  in significantly increased RAC1-GTP levels"]. These are read-outs of reduced Rac1
  activation, not GTP hydrolysis by RhoGDI2.
• Cancer: PMID:12438227.
• Knockout mice largely normal: PMID:9307064; PMID:9307064.
  Partial redundancy with RhoGDI1 is likely.
• Caspase-3 substrate in apoptosis: PMID:11989976

Localization

• Cytosol: UniProt "Cytoplasm, cytosol {ECO:0000269|PubMed:10802295}"; bovine
  neutrophil cytosol PMID:10802295.
• GFP-D4 is diffuse cytoplasmic, unlike RhoGDIγ: PMID:9113980. The cytoplasmic vesicle localisation in that paper is for RhoGDIγ
  (ARHGDIG), so the PINC TAS row "cytoplasmic vesicle" for ARHGDIB from PMID:9113980 is
  attached to the wrong paralog.
• PMID:16130169 (HUVEC 2-DE proteome) is a protein inventory; it does not establish
  cytoskeletal localisation.

Decision on the flagged GO:0003924 row

The abstract of PMID:24554735 measures RAC1-GTP levels after RhoGDI2 over-expression or
knockdown; that is inhibition of Rac1 activation, the expected consequence of GDI
activity. Nothing reported is GTP hydrolysis catalysed by RhoGDI2, and the protein has
no GTPase fold. Action: MODIFY to GO:0005094 Rho GDP-dissociation inhibitor activity,
with a source_defects WRONG_TERM entry for CACAO (confidence PROBABLE because only the
abstract is cached).

Open questions

• Physiological target selectivity of RhoGDI2 among RAC2/RAC1/RHOA/CDC42 in leukocytes.
• Role of Src-mediated tyrosine phosphorylation and caspase cleavage in GDI function.