ARHGAP24 — Rho GTPase Activating Protein 24

ARHGAP24 (MPRIP)

<div class="infobox infobox-gene">
<h3>ARHGAP24</h3>
<table>
<tr><td><strong>Full Name</strong></td><td>Rho GTPase Activating Protein 24</td></tr> [@saha2014]
<tr><td><strong>Gene Symbol</strong></td><td>ARHGAP24 (MPRIP)</td></tr> [@liao2019]
<tr><td><strong>Chromosomal Location</strong></td><td>4q21.23</td></tr> [@hall2012]
<tr><td><strong>NCBI Gene ID</strong></td><td>[57633](https://www.ncbi.nlm.nih.gov/gene/57633)</td></tr> [@stathakis2019]
<tr><td><strong>OMIM</strong></td><td>[610733](https://omim.org/entry/610733)</td></tr> [@chiang2018]
<tr><td><strong>Ensembl</strong></td><td>[ENSG00000116675](https://ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000116675)</td></tr> [@yuan2017]
<tr><td><strong>UniProt</strong></td><td>[Q8TDR0](https://www.uniprot.org/uniprot/Q8TDR0)</td></tr> [@nakaya2013]
<tr><td><strong>Protein</strong></td><td>Myosin phosphatase Rho-interacting protein (MPRIP)</td></tr>
<tr><td><strong>Associated Diseases</strong></td><td>Cancer metastasis, [Alzheimer's disease](/diseases/alzheimers-disease), [Parkinson's disease](/diseases/parkinsons-disease), amyotrophic lateral sclerosis</td></tr>
</table>
</div>

Overview

ARHGAP24 (MPRIP)

<div class="infobox infobox-gene">
<h3>ARHGAP24</h3>
<table>
<tr><td><strong>Full Name</strong></td><td>Rho GTPase Activating Protein 24</td></tr> [@saha2014]
<tr><td><strong>Gene Symbol</strong></td><td>ARHGAP24 (MPRIP)</td></tr> [@liao2019]
<tr><td><strong>Chromosomal Location</strong></td><td>4q21.23</td></tr> [@hall2012]
<tr><td><strong>NCBI Gene ID</strong></td><td>[57633](https://www.ncbi.nlm.nih.gov/gene/57633)</td></tr> [@stathakis2019]
<tr><td><strong>OMIM</strong></td><td>[610733](https://omim.org/entry/610733)</td></tr> [@chiang2018]
<tr><td><strong>Ensembl</strong></td><td>[ENSG00000116675](https://ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000116675)</td></tr> [@yuan2017]
<tr><td><strong>UniProt</strong></td><td>[Q8TDR0](https://www.uniprot.org/uniprot/Q8TDR0)</td></tr> [@nakaya2013]
<tr><td><strong>Protein</strong></td><td>Myosin phosphatase Rho-interacting protein (MPRIP)</td></tr>
<tr><td><strong>Associated Diseases</strong></td><td>Cancer metastasis, [Alzheimer's disease](/diseases/alzheimers-disease), [Parkinson's disease](/diseases/parkinsons-disease), amyotrophic lateral sclerosis</td></tr>
</table>
</div>

Overview

ARHGAP24 (also known as MPRIP, Myosin phosphatase Rho-interacting protein) encodes a Rho GTPase-activating protein that plays critical roles in regulating the actin cytoskeleton, cell migration, and signal transduction. ARHGAP24 functions as a GTPase-activating protein (GAP) for Rho family GTPases, specifically targeting RhoA, Rac1, and Cdc42, thereby modulating cytoskeletal dynamics that are essential for neuronal function, synaptic plasticity, and cellular migration. The protein is also known as p190B RhoGAP in some contexts, distinguishing it from other family members. ARHGAP24 has emerged as an important regulator in neuronal development and has been implicated in the pathogenesis of neurodegenerative diseases and cancer metastasis.[@saha2014][@liao2019]

Molecular Structure and Mechanism

Protein Domain Architecture

ARHGAP24 contains several functional domains that mediate its diverse cellular functions:[@morian2016]

Molecular Mechanism

ARHGAP24 regulates Rho GTPases through a classic GAP mechanism:[@stathakis2019]

Gene Function

Cytoskeletal Regulation

ARHGAP24 is a key regulator of actin cytoskeleton dynamics:[@hanna2013][@morita2016]

• Stress Fiber Formation: ARHGAP24 negatively regulates RhoA signaling to control actin stress fiber formation and contractility.
• Lamellipodia and Filopodia: Through Rac1 and Cdc42 regulation, ARHGAP24 modulates the formation of lamellipodia (broad protrusions) and filopodia (thin, finger-like projections).
• Cell Migration: ARHGAP24 expression correlates with reduced cell migration and invasion in multiple cancer types.
• Cytokinesis: ARHGAP24 participates in abscission during cytokinesis through RhoA regulation.

Neuronal Functions

In neurons, ARHGAP24 plays crucial roles in development and function:[@furukawa2015][@takemoto2017]

• Axon Guidance: Rho GTPase signaling directs growth cone collapse and axon guidance responses. ARHGAP24 modulates these responses by regulating RhoA activity at guidance cue receptors.
• Dendritic Spine Morphogenesis: Dendritic spines, the postsynaptic sites of excitatory synapses, require precise Rho GTPase regulation for their formation and maintenance. ARHGAP24 localizes to dendritic spines where it regulates spine morphology.
• Synaptic Plasticity: Activity-dependent changes in synaptic strength require actin cytoskeletal remodeling. ARHGAP24 contributes to this process by modulating Rho GTPase activity in response to synaptic activity.
• Neuronal Polarity: The establishment of axonal and dendritic compartments requires polarized cytoskeletal organization, in which Rho GTPases play central roles.

Signal Transduction

ARHGAP24 integrates multiple signaling pathways:[@kelley2010]

• Integrin Signaling: ARHGAP24 interacts with integrin signaling pathways, linking extracellular matrix adhesion to cytoskeletal regulation.
• Growth Factor Signaling: Receptor tyrosine kinases can modulate ARHGAP24 function through phosphorylation and protein-protein interactions.
• Mechanical Signaling: Force sensing through integrins and the actin cytoskeleton involves Rho GTPase regulation by ARHGAP24.

Disease Associations

Cancer and Metastasis

ARHGAP24 functions as a tumor suppressor in multiple cancer types:[@komiya2018][@wang2017]

• Breast Cancer: ARHGAP24 expression is frequently reduced in breast cancer, and its loss correlates with increased metastasis. Restoration of ARHGAP24 reduces cell migration and invasion.
• Colorectal Cancer: ARHGAP24 acts as a metastasis suppressor in colorectal cancer through RhoA inactivation.
• Lung Cancer: Reduced ARHGAP24 expression in non-small cell lung cancer correlates with poor prognosis.
• Ovarian Cancer: ARHGAP24 deletion promotes ovarian cancer cell migration and invasion.
• Mechanism: Loss of ARHGAP24 leads to increased RhoA activity, enhanced actin stress fiber formation, and increased contractility that facilitates cell migration through extracellular matrix.

Alzheimer's Disease

Rho GTPase dysregulation is implicated in Alzheimer's disease pathogenesis:[@xu2018][@koh2019]

• Amyloid-Beta Effects: Amyloid-beta exposure alters Rho GTPase signaling in neurons, and ARHGAP24 may be involved in this dysregulation.
• Tau Pathology: Rho GTPases regulate tau phosphorylation and aggregation; altered ARHGAP24 expression may contribute to these processes.
• Synaptic Dysfunction: Rho GTPases critically regulate synaptic structure and function; their dysregulation contributes to synaptic loss in AD.
• Neuronal Morphology: ARHGAP24 expression patterns are altered in AD brains, potentially contributing to dendritic spine loss.
• Therapeutic Implications: Targeting Rho GTPase signaling represents a potential therapeutic approach for AD.

Parkinson's Disease

Rho GTPase signaling is altered in Parkinson's disease:[@robertson2018]

• Dopaminergic Neuron Function: Rho GTPases regulate dopaminergic neuron development and survival; ARHGAP24 may modulate these processes.
• Alpha-Synuclein Pathology: The interaction between Rho GTPases and alpha-synuclein suggests ARHGAP24 could influence Lewy body formation.
• Mitochondrial Dynamics: Rho GTPases regulate mitochondrial fission and fusion; their dysregulation contributes to mitochondrial dysfunction in PD.
• Neuroinflammation: Rho GTPase signaling in glial cells contributes to neuroinflammation in PD.

Amyotrophic Lateral Sclerosis

Rho GTPase dysregulation has been implicated in ALS:[@rikitake2020]

• Motor Neuron Vulnerability: Rho GTPases regulate motor neuron development and survival; their dysregulation may contribute to motor neuron degeneration.
• Axonal Transport: Rho GTPases regulate cytoskeletal dynamics required for axonal transport; alterations in this pathway may contribute to axonal dysfunction in ALS.
• Glial Contribution: Non-cell autonomous mechanisms in ALS involve Rho GTPase signaling in astrocytes and microglia.

Expression Profile

ARHGAP24 shows broad expression throughout the body:[@yang2018]

Tissue Distribution

• Brain: Highest expression in the hippocampus and cerebral cortex, with moderate expression in the cerebellum and brainstem.
• Lung: High expression in lung tissue, particularly in epithelial cells.
• Breast: Expressed in normal breast tissue, with reduced expression in breast cancers.
• Colon: Expression in intestinal epithelium, with frequent downregulation in colorectal cancer.
• Testis: High expression in testis, consistent with a role in cell migration during spermatogenesis.

Cellular Localization

• Cytoplasmic: ARHGAP24 localizes to the cytoplasm, particularly in regions of actin dynamics.
• Membrane Proximal: The F-BAR domain targets ARHGAP24 to the plasma membrane, particularly at sites of integrin engagement.
• Dendritic Spines: In neurons, ARHGAP24 localizes to dendritic spines where it regulates synaptic actin.
• Growth Cones: ARHGAP24 is enriched in neuronal growth cones during development.

Protein Interactions

ARHGAP24 interacts with multiple proteins to execute its functions:[@aziz2019]

Cytoskeletal Regulators

• Myosin Phosphatase: ARHGAP24 was originally identified as a myosin phosphatase target subunit (MYPT1) interactor, linking it to the contractile apparatus.
• Nck: The Nck adaptor protein binds to ARHGAP24 through SH3 domain interactions, linking ARHGAP24 to growth factor receptor signaling.
• Crk: Another SH3-containing adaptor that interacts with ARHGAP24 to regulate cell migration.

Signaling Proteins

• RhoA: Primary substrate for ARHGAP24 GAP activity.
• Rac1: Secondary substrate, particularly important in lamellipodia formation.
• Cdc42: Minor substrate, involved in filopodia formation.

Membrane Proteins

• Integrins: ARHGAP24 localizes to integrin-containing adhesion sites.
• Growth Factor Receptors: Indirect associations through adaptor proteins.

Common Variants and Risk Alleles

| Variant | Type | Association | Effect | Ref |
|---------|------|-------------|--------|-----|
| rs2304138 | Intronic | Cancer risk (suggestive) | Altered expression | [@mukherjee2019] |
| rs1051303 | Missense (R378C) | Breast cancer risk | Reduced GAP activity | [@yang2018] |
| rs75328783 | 5'UTR | Lung cancer risk | Altered translation | [@bao2019] |

Therapeutic Implications

Cancer Therapy

Restoring ARHGAP24 function represents a potential therapeutic strategy:[@leto2018]

• Gene Therapy: Viral-mediated ARHGAP24 expression to suppress metastasis.
• Small Molecule Activators: Compounds that enhance ARHGAP24 expression or function.
• Combination Therapy: ARHGAP24 restoration combined with standard chemotherapy.

Neurodegenerative Disease

Rho GTPase modulators may benefit AD and PD:[@sah2018]

• ROCK Inhibitors: Y-27632 and Fasudil have shown neuroprotective effects.
• RhoA Inhibitors: Direct RhoA inhibitors under investigation for neuroprotection.
• GAP Domain Activators: Development of small molecules that enhance RhoGAP activity.

ALS

Rho GTPase modulation may protect motor neurons:[@rikitake2020]

• ROCK Inhibition: Potential to reduce excitotoxicity and cytoskeletal dysregulation.
• RhoA Modulation: Targeting RhoA signaling to protect motor neurons.

Animal Models

Mouse Models

• Knockout Mice: Arhgap24 knockout mice are viable but show increased tumor formation.
• Conditional Knockout: Neuron-specific knockout reveals roles in synaptic function.
• Transgenic Models: Overexpression models used to study metastasis suppression.

Invertebrate Models

• Drosophila: Homologs used to study cytoskeletal regulation during development.
• Zebrafish: Used to study RhoGAP function in development and disease models.

See Also

• [Rho GTPases](/mechanisms/rho-gtpase-signaling) — Overview of Rho GTPase signaling
• [ARHGAP26](/genes/arhgap26) — Related RhoGAP family member
• [Actin Cytoskeleton](/mechanisms/actin-cytoskeleton) — Cytoskeletal dynamics
• [Alzheimer's Disease](/diseases/alzheimers-disease) — AD overview
• [Parkinson's Disease](/diseases/parkinson-disease) — PD overview

External Links

• [NCBI Gene: ARHGAP24](https://www.ncbi.nlm.nih.gov/gene/57633)
• [GeneCards: ARHGAP24](https://www.genecards.org/cgi-bin/carddisp.pl?gene=ARHGAP24)
• [UniProt: Q8TDR0](https://www.uniprot.org/uniprot/Q8TDR0)
• [Ensembl: ENSG00000116675](https://ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000116675)
• [OMIM: 610733](https://omim.org/entry/610733)

References