Affinage

GMIP

GEM-interacting protein · UniProt Q9P107

Length
970 aa
Mass
106.7 kDa
Annotated
2026-04-28
21 papers in source corpus 9 papers cited in narrative 9 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

GMIP is a RhoA-specific GTPase-activating protein that couples membrane-associated signaling to local actin remodeling across multiple cellular contexts, including cell morphology, secretory vesicle exocytosis, neuronal migration, and mitotic spindle positioning. GMIP binds the Ras-related GTPase Gem via its N-terminal half and functions downstream of Gem to inactivate RhoA, thereby depolymerizing cortical actin stress fibers and dismantling focal adhesions; the morphological effects of Gem require GMIP expression and membrane enrichment (PMID:12093360, PMID:17267693). GMIP also associates with the Rab27a effector JFC1 to locally inactivate RhoA around secretory granules, enabling their passage through cortical actin for exocytosis, and localizes to the proximal leading process of migrating postnatal neurons where it controls saltatory movement speed and neuronal stop position (PMID:22438581, PMID:25074242). GMIP contains a conserved F-BAR domain with a phosphoinositide-binding site for membrane targeting, a pLxIS motif through which it stimulates interferon responses independently of known pattern-recognition receptors, and its RhoGAP domain is specifically active toward RhoA but not Rac1 or Cdc42 (PMID:25620000, PMID:38925114, PMID:12093360).

Mechanistic history

Synthesis pass · year-by-year structured walk · 8 steps
  1. 2002 High

    The first mechanistic question—what is GMIP's enzymatic activity and protein partner—was answered by showing it is a RhoA-specific GAP that binds Gem, establishing GMIP as a link between Gem signaling and RhoA inactivation.

    Evidence Yeast two-hybrid screen, in vitro GTPase assays with RhoA/Rac1/Cdc42, stress fiber assay in Ref-52 fibroblasts

    PMID:12093360

    Open questions at the time
    • Mechanism of Gem-dependent regulation of GMIP GAP activity not defined
    • No structural information on the GMIP GAP domain
    • Physiological context of Gem–GMIP signaling unknown
  2. 2007 High

    How Gem uses GMIP in a cellular context was resolved: GTP-bound Gem recruits GMIP to membranes via Ezrin to locally inactivate RhoA, dismantle stress fibers and focal adhesions, and drive cell elongation—establishing GMIP as an obligate effector of Gem-induced morphological remodeling.

    Evidence Reciprocal co-immunoprecipitation, membrane fractionation, dominant-negative/constitutively-active mutants, immunofluorescence in mammalian cells

    PMID:17267693

    Open questions at the time
    • Direct biochemical mechanism by which Gem activates or localizes GMIP's GAP activity unresolved
    • Whether GMIP has Gem-independent functions in vivo not addressed
  3. 2012 High

    A Gem-independent function was uncovered: GMIP associates with the Rab27a effector JFC1 and locally inactivates RhoA around secretory granules, depolymerizing cortical actin to enable vesicular transport and exocytosis in neutrophils.

    Evidence Proteomic pulldown confirmed by co-IP, siRNA knockdown, RhoA activity assays, live-cell microscopy, JFC1 knockout neutrophils

    PMID:22438581

    Open questions at the time
    • Whether JFC1 directly recruits GMIP to granule membranes or an intermediate is involved
    • Relative contributions of Gem-dependent versus JFC1-dependent GMIP pools not determined
  4. 2014 High

    GMIP's in vivo physiological role in the brain was established: it localizes to the proximal leading process of migrating postnatal neurons and locally inactivates RhoA to control saltatory migration speed and neuronal stop position, affecting neural circuit formation.

    Evidence In vivo knockdown/knockout in mouse brain, live imaging of neuron migration, RhoA activity assays, immunolocalization

    PMID:25074242

    Open questions at the time
    • Upstream signals directing GMIP localization within the leading process unknown
    • Whether Gem or another partner activates GMIP during neuronal migration not tested
  5. 2014 High

    The Gem–GMIP–RhoA axis was placed in mitosis: epistasis experiments showed Gem acts upstream of GMIP to inactivate RhoA and remodel cortical actin for proper spindle positioning, establishing a role for this pathway in cell division.

    Evidence siRNA knockdown, overexpression of dominant-negative and constitutively-active RhoA, immunofluorescence of mitotic spindles

    PMID:25173885

    Open questions at the time
    • Temporal regulation of Gem–GMIP during mitotic entry not defined
    • Whether spindle mispositioning affects cell fate decisions not examined
  6. 2014 Medium

    An unexpected connection to cell cycle regulation emerged: EBV protein BGLF2 targets GMIP, and GMIP silencing induces p21 in a p53-independent manner, suggesting GMIP restrains p21 levels under normal conditions.

    Evidence BGLF2 interactome by proteomics, siRNA knockdown, Western blot for p21/p53, flow cytometry

    PMID:24501404

    Open questions at the time
    • Mechanism linking GMIP's GAP activity to p21 regulation completely unresolved
    • Whether RhoA inactivation is the relevant pathway for p21 suppression not tested
    • Single study without independent confirmation
  7. 2015 Medium

    Structural insight into GMIP's membrane targeting was provided: crystallography of the yeast ortholog Rgd1p revealed an F-BAR domain phosphoinositide-binding site fully conserved in GMIP, explaining how GMIP associates with membranes.

    Evidence X-ray crystallography of Rgd1p F-BAR domain with inositol phosphate, sequence conservation analysis

    PMID:25620000

    Open questions at the time
    • Direct structural or lipid-binding data for the GMIP F-BAR domain itself not obtained
    • Which specific phosphoinositide species GMIP binds in mammalian cells unknown
  8. 2024 Medium

    A GAP-independent signaling function was discovered: GMIP stimulates interferon responses via a pLxIS motif independently of all known pattern-recognition receptor pathways, revealing an unexpected role in innate immunity.

    Evidence Synthetic biology screening platform, IFN reporter assays in human cells

    PMID:38925114

    Open questions at the time
    • Whether GMIP's pLxIS-mediated IFN signaling requires or is separate from its RhoGAP activity
    • Physiological contexts (infection, sterile inflammation) where this function operates not defined
    • Downstream signaling cascade from GMIP pLxIS to IRF activation not fully mapped

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key open questions remain: how GMIP's RhoGAP and pLxIS/innate immune functions are coordinated, what upstream signals spatiotemporally regulate GMIP in different cellular contexts, and whether its F-BAR domain directly binds specific phosphoinositides in mammalian cells.
  • No structure of mammalian GMIP available
  • Integration of GAP-dependent and GAP-independent functions not studied
  • In vivo validation of innate immune function lacking

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 5 GO:0140096 catalytic activity, acting on a protein 2
Localization
GO:0005856 cytoskeleton 2 GO:0005886 plasma membrane 2 GO:0031410 cytoplasmic vesicle 1
Pathway
R-HSA-162582 Signal Transduction 4 GO:0005856 cytoskeleton 1 R-HSA-1266738 Developmental Biology 1 R-HSA-168256 Immune System 1
Partners
BGLF2EZRGEMJFC1RHOA

Evidence

Reading pass · 9 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2002 GMIP was identified as a novel RhoA-specific GTPase-activating protein (RhoGAP) that interacts with Gem (a Ras-related protein) through its N-terminal half. The RhoGAP domain of GMIP stimulates GTPase activity of RhoA in vitro but is inactive towards Rac1 and Cdc42. Full-length GMIP down-regulates RhoA-dependent stress fibres in Ref-52 rat fibroblasts. Yeast two-hybrid screen, in vitro GTPase assay, cell-based stress fibre assay The Biochemical journal High 12093360
2007 GTP-bound Gem interacts with active Ezrin at the plasma membrane-cytoskeleton interface, and Gem acts via its RhoGAP partner GMIP to down-regulate RhoA activity, actin stress fibres, and focal adhesions. GMIP is enriched in membranes under conditions where Gem induces cell elongation, and the morphological effects of Gem require GMIP expression. Co-immunoprecipitation, dominant-negative and constitutively active mutants, immunofluorescence, membrane fractionation Molecular biology of the cell High 17267693
2012 GMIP associates with the Rab27a effector JFC1 (identified by proteomics) and regulates vesicular transport and exocytosis. GMIP down-regulation induces RhoA activation and actin polymerization, impairing vesicular transport through cortical actin. RhoA activity polarizes around JFC1-containing secretory granules, and JFC1 knockout neutrophils show increased RhoA activity with azurophilic granules unable to traverse cortical actin. Proteomic pulldown/Co-IP, siRNA knockdown, RhoA activity assays, quantitative live-cell microscopy, JFC1 knockout cells Molecular biology of the cell High 22438581
2014 Gmip, a RhoA-specific GAP, localizes to the proximal leading process of migrating neurons in the postnatal brain and locally inactivates RhoA to control the saltatory movement and speed of neuronal migration from the ventricular-subventricular zone to the olfactory bulb. Loss of Gmip alters neuronal 'stop' positions and neural circuitry. In vivo loss-of-function (knockdown/knockout), live imaging of migrating neurons, RhoA activity assays, immunolocalization Nature communications High 25074242
2014 Gem acts upstream of Gmip and RhoA to regulate cortical actin remodeling and spindle positioning during early mitosis. Ectopic Gem expression causes cortical actin disruption and spindle mispositioning; Gmip knockdown rescues these defects. Dominant-negative RhoA prevents normal spindle positioning, while active RhoA rescues actin and spindle defects caused by Gem or Gmip overexpression, placing RhoA downstream of Gem/Gmip. siRNA knockdown, overexpression of dominant-negative and constitutively active RhoA mutants, immunofluorescence of mitotic cells Carcinogenesis High 25173885
2015 The F-BAR domain of the yeast RhoGAP Rgd1p was crystallized bound to an inositol phosphate, revealing a phosphoinositide-binding site that is fully conserved in mammalian GMIP, indicating GMIP possesses an F-BAR domain with a conserved phosphoinositide-binding site for membrane association. X-ray crystallography, sequence conservation analysis, in vitro lipid-binding assays Structure Medium 25620000
2014 The EBV tegument protein BGLF2 interacts with GMIP (and NEK9), and silencing of GMIP induces p21 protein levels in a p53-independent manner. GMIP silencing abrogates the ability of BGLF2 to further induce p21, placing GMIP as a regulator of p21 that is targeted by BGLF2 to induce G1/S arrest. Proteomic analysis (BGLF2 interactome), siRNA knockdown of GMIP, flow cytometry cell cycle analysis, Western blot for p21/p53 Journal of virology Medium 24501404
2020 GMIP overexpression attenuates lung cancer cell migration, and GMIP is hypermethylated (silenced) by the RASSF1C-PIWIL1-piRNA pathway in NSCLC cells, suggesting GMIP acts as a tumor suppressor downstream of this epigenetic pathway. RRBS methylation profiling, overexpression migration assay, RASSF1C/PIWIL1 knockdown Oncotarget Low 33227088
2024 GMIP was identified as one of two orphan pLxIS-motif-containing proteins that stimulate interferon responses independent of all known pattern-recognition receptor pathways, expanding the known signaling repertoire of pLxIS/ARIES domain proteins. Synthetic biology-based screening platform, IFN reporter assays in human cells Molecular cell Medium 38925114

Source papers

Stage 0 corpus · 21 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2011 Molecular markers of endometrial carcinoma detected in uterine aspirates. International journal of cancer 99 21207424
2012 Vesicular trafficking through cortical actin during exocytosis is regulated by the Rab27a effector JFC1/Slp1 and the RhoA-GTPase-activating protein Gem-interacting protein. Molecular biology of the cell 83 22438581
2014 Speed control for neuronal migration in the postnatal brain by Gmip-mediated local inactivation of RhoA. Nature communications 50 25074242
2002 A novel Rho GTPase-activating-protein interacts with Gem, a member of the Ras superfamily of GTPases. The Biochemical journal 48 12093360
2014 Identification of herpesvirus proteins that contribute to G1/S arrest. Journal of virology 43 24501404
2007 Gem associates with Ezrin and acts via the Rho-GAP protein Gmip to down-regulate the Rho pathway. Molecular biology of the cell 43 17267693
2005 Gene profiling involved in immature CD4+ T lymphocyte responsible for systemic lupus erythematosus. Molecular immunology 39 16143398
2015 Comparison of Saccharomyces cerevisiae F-BAR domain structures reveals a conserved inositol phosphate binding site. Structure (London, England : 1993) 35 25620000
2004 Identification and characterization of ARHGAP27 gene in silico. International journal of molecular medicine 33 15492870
2004 Characterization of human ARHGAP10 gene in silico. International journal of oncology 27 15375573
2020 The impact of the RASSF1C and PIWIL1 on DNA methylation: the identification of GMIP as a tumor suppressor. Oncotarget 14 33227088
2005 The Gem interacting protein (GMIP) gene is associated with major depressive disorder. Neurogenetics 14 16086184
2014 Gem GTPase acts upstream Gmip/RhoA to regulate cortical actin remodeling and spindle positioning during early mitosis. Carcinogenesis 12 25173885
2024 DeLIVR: a deep learning approach to IV regression for testing nonlinear causal effects in transcriptome-wide association studies. Biostatistics (Oxford, England) 11 36610078
2018 Ganoderma microsporum immunomodulatory protein induces apoptosis and potentiates mitomycin C-induced apoptosis in urinary bladder urothelial carcinoma cells. Journal of cellular biochemistry 11 29240252
2024 pLxIS-containing domains are biochemically flexible regulators of interferons and metabolism. Molecular cell 7 38925114
1998 Iodopyridine-for-iodobenzene substitution for use with low molecular weight radiopharmaceuticals: application to m-iodobenzylguanidine. Bioconjugate chemistry 7 9815170
2020 Identification of pleiotropic genes between risk factors of stroke by multivariate metaCCA analysis. Molecular genetics and genomics : MGG 6 32474671
2025 ARIES domains: functional signaling units of type I interferon responses. The FEBS journal 2 39964808
2000 Long-lasting cyclic guanosine-3',5'-monophosphate accumulation in the medium of cultured smooth muscle cells from atherosclerotic rabbit aortas in response to exogenous or endogenous nitric oxide. Fundamental & clinical pharmacology 2 11129085
2025 Decoding the triglyceride-glucose index in metabolic dysfunction-associated steatotic liver disease: integrative insights from Mendelian randomization, cross-tissue transcriptomics, and spatial multi-omics. International journal of surgery (London, England) 0 41056021