RRAS1 Gene

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RRAS1 Gene

<table class="infobox infobox-gene">
<tr>
<th class="infobox-header" colspan="2">RRAS1 Gene</th>
</tr>
<tr>
<td class="label">Gene Symbol</td>
<td>RRAS1</td>
</tr>
<tr>
<td class="label">Full Name</td>
<td>Related RAS Viral Oncogene Homolog 1</td>
</tr>
<tr>
<td class="label">Alternative Names</td>
<td>R-Ras1, RRAS, R-RAS1</td>
</tr>
<tr>
<td class="label">Chromosomal Location</td>
<td>19q13.33</td>
</tr>
<tr>
<td class="label">NCBI Gene ID</td>
<td>10539</td>
</tr>
<tr>
<td class="label">Ensembl ID</td>
<td>ENSG00000155070</td>
</tr>
<tr>
<td class="label">UniProt ID</td>
<td>P10301</td>
</tr>
<tr>
<td class="label">OMIM</td>
<td>165090</td>
</tr>
<tr>
<td class="label">Protein Class</td>
<td>Small GTPase; Ras family</td>
</tr>
<tr>
<td class="label">Associated Diseases</td>
<td>Alzheimer's disease, Parkinson's disease, various cancers</td>
</tr>
<tr>
<td class="label">Interactor</td>
<td>Interaction Type</td>
</tr>
<tr>
<td class="label">Integrins (αvβ3, α5β1)</td>
<td>Effector</td>
</tr>
<tr>
<td class="label">PI3K</td>
<td>Effector</td>
</tr>
<tr>
<td class="label">FAK</td>
<td>Effector</td>
</tr>
<tr>
<td class="label">RASGRF1</td>
<td>GEF</td>
</tr>
<tr>
<td class="label">RASGRP1</td>
<td>GEF</td>
</tr>
<tr>
<td class="label">p120GAP</td>
<td>GAP</td>
</tr>
<tr>
<td class="label">NF1</td>
<td>GAP</

...

RRAS1 Gene

RRAS1 (Related RAS Viral Oncogene Homolog 1), also known as R-Ras1, is a member of the small GTPase superfamily belonging to the R-Ras subfamily of Ras GTPases. Located on chromosome 19q13.33, RRAS1 regulates critical cellular processes including cell adhesion, migration, proliferation, and survival. In the nervous system, RRAS1 plays essential roles in neuronal development, synaptic plasticity, and axonal guidance. Growing evidence links RRAS1 dysfunction to [Alzheimer's disease](/diseases/alzheimers-disease), [Parkinson's disease](/diseases/parkinsons-disease), and various cancers.

Overview

Gene Structure

The RRAS1 gene spans approximately 25 kb and consists of 6 exons encoding a 218-amino acid protein. The gene is highly conserved across mammals and exhibits broad tissue expression with particularly high levels in brain, heart, and vascular tissue.

Protein Structure

RRAS1 shares structural homology with other Ras GTPases:

G-domain — The N-terminal region (amino acids 1-166) contains the GTP/GDP-binding pocket with conserved motifs for nucleotide binding and hydrolysis.

Switch I region — Amino acids 25-40, undergoes conformational changes between GTP- and GDP-bound states, mediating effector interactions.

Switch II region — Amino acids 58-72, critical for GAP and GEF interactions.

C-terminal hypervariable region — Amino acids 165-190, contains the CAAX motif (Cys-Alaa-Ala-X) for prenylation and membrane localization.

C-terminal tail — The final 20 amino acids mediate membrane anchoring through farnesylation.

Function

GTPase Cycle

RRAS1 functions as a molecular switch:

GTP-bound state — Active, can interact with downstream effectors
GDP-bound state — Inactive, unable to signal
GTP hydrolysis — Converted to GDP by intrinsic GTPase activity, accelerated by GAPs (GTase-Activating Proteins)
GDP/GTP exchange — Stimulated by GEFs (Guanine nucleotide Exchange Factors)

Cell Adhesion and Migration

RRAS1 regulates integrin-mediated adhesion:

Integrin activation — RRAS1 promotes integrin affinity for extracellular matrix
FAK signaling — Activates Focal Adhesion Kinase pathway
Actin cytoskeleton — Modulates actin dynamics at adhesion sites
Cell migration — Controls directional migration through integrin signaling

Neuronal Functions

In neurons, RRAS1 is critical for:

Neurite outgrowth — RRAS1 promotes axonal and dendritic extension
Axonal guidance — Modulates growth cone responses to guidance cues
Synaptic plasticity — Regulates spine formation and function
Dendritic spine morphology — Controls spine shape and stability
Synaptic transmission — Modulates neurotransmitter release

Cell Survival

RRAS1 influences cell survival pathways:

PI3K/Akt signaling — Activates pro-survival signaling
MAPK pathway — Modulates cell proliferation
Apoptosis regulation — Can protect against apoptotic stimuli

Brain Expression

RRAS1 is widely expressed in the brain:

Cerebral cortex — Pyramidal neurons in layers II-VI
Hippocampus — CA1-CA3 pyramidal cells, dentate gyrus granule cells
Cerebellum — Purkinje cells, granule cells
Basal ganglia — Striatal medium spiny neurons
Thalamus and hypothalamus — Various neuronal populations
Olfactory bulb — Mitral and tufted cells
Peripheral nervous system — Sensory and motor neurons

Cellular Localization

In neurons, RRAS1 localizes to:

Dendritic shafts and spines
Axonal compartments
Growth cones
Postsynaptic densities
Presynaptic terminals

Molecular Mechanisms

Signaling Pathways

RRAS1 activates multiple downstream pathways:

PI3K/Akt pathway

RRAS1 activates PI3K (particularly PI3Kγ)
Leads to Akt phosphorylation and activation
Promotes cell survival and growth

MAPK/ERK pathway

RRAS1 can activate Raf-1 through Ras family cascades
Promotes cell proliferation and differentiation

FAK pathway

Activates Focal Adhesion Kinase
Regulates integrin signaling and adhesion

Ral pathway

Can activate RalGEFs
Affects actin cytoskeleton and vesicle trafficking

Integrin Signaling

RRAS1 is a key regulator of integrin function:

Inside-out signaling — RRAS1 promotes integrin activation from within
Affinity modulation — Increases integrin affinity for ligands
Clustering — Facilitates integrin cluster formation
Outside-in signaling — Modulates downstream signaling upon ligand binding

Synaptic Plasticity

RRAS1 regulates synaptic changes[@johnson2020]:

Long-term potentiation (LTP) — Required for LTP in hippocampal neurons
Long-term depression (LTD) — Modulates LTD mechanisms
Spine remodeling — Controls actin dynamics in dendritic spines
AMPA receptor trafficking — Regulates GluA1 subunit trafficking

RRAS1 in Synaptic Function

Activity-dependent RRAS1 signaling is critical for synaptic plasticity:

Calcium influx: Synaptic activity triggers calcium influx through NMDA receptors

GEF activation: Calcium activates RASGRF GEFs that stimulate RRAS1

Downstream signaling: RRAS1 activates PI3K and Akt to support LTP

Spine stabilization: RRAS1 promotes actin polymerization in spines [@zhang2021]

This pathway is impaired in AD, contributing to memory deficits [@chen2023].

Regulation

RRAS1 activity is tightly regulated:

Guanine Nucleotide Exchange Factors (GEFs)

Multiple GEFs activate RRAS1[yang2019]:

RASGRF1/2 — Calcium-responsive GEFs
RASGRP1-4 — Diacylglycerol-regulated GEFs
SOS1/2 — Can activate RRAS1 in certain contexts

GTPase-Activating Proteins (GAPs)

Several GAPs inactivate RRAS1:

p120GAP — Classical Ras GAP with activity toward RRAS1
NF1 — Neurofibromin, tumor suppressor
RASA1-3 — Synaptic GAPs

Post-translational Modifications

Farnesylation — C-terminal CAAX motif farnesylation for membrane localization
Palmitoylation — Additional palmitoylation in some isoforms
Phosphorylation — Can modulate effector interactions

Disease Associations

Alzheimer's Disease

RRAS1 is implicated in [Alzheimer's disease](/diseases/alzheimers-disease) through multiple mechanisms:

Amyloid-beta effects — Aβ can alter RRAS1 signaling in neurons
Synaptic dysfunction — RRAS1 contributes to spine loss in AD
Tau pathology — RRAS1 may intersect with tau phosphorylation pathways
Neuronal survival — RRAS1-mediated survival signals are compromised in AD
Neuroinflammation — RRAS1 regulates microglial migration

Molecular Mechanisms in AD

RRAS1 contributes to Alzheimer's disease through specific molecular pathways:

Amyloid-beta signaling: Aβ oligomers interact with integrin receptors that signal through RRAS1, leading to dysregulated actin cytoskeleton and spine loss[@wang2022].

PI3K/Akt pathway impairment: RRAS1-mediated Akt activation is compromised in AD, reducing pro-survival signaling in neurons[@liu2022].

Integrin dysfunction: RRAS1 requires functional integrins for its neuroprotective effects; Aβ-induced integrin dysfunction impairs RRAS1 signaling.

Synaptic RRAS1 signaling: Activity-dependent RRAS1 activation at synapses is required for LTP; this signaling is disrupted in AD models.

Microglial migration: RRAS1 regulates microglial chemotaxis; dysregulation contributes to neuroinflammatory responses in AD.

Parkinson's Disease

RRAS1 may contribute to [Parkinson's disease](/diseases/parkinsons-disease) through[@liu2023][@park2022][@wong2021]:

Dopaminergic neuron survival — RRAS1 supports nigral neuron viability[@park2022]
Alpha-synuclein interactions — RRAS1 may be affected by α-syn aggregation[@liu2023]
Axonal transport — RRAS1 regulates microtubule-based transport
Mitochondrial function — RRAS1 influences mitochondrial dynamics[@wong2021]

Cancer

Dysregulated RRAS1 signaling is associated with multiple cancers:

Oncogenic activation — RRAS1 can promote tumor cell proliferation
Metastasis — RRAS1 enhances cell migration and invasion
Angiogenesis — RRAS1 contributes to tumor vascularization
Resistance — RRAS1 can confer resistance to targeted therapies

Other Neurological Conditions

Amyotrophic lateral sclerosis — RRAS1 in motor neuron function
Schizophrenia — Altered RRAS1 signaling in prefrontal cortex
Intellectual disability — RRAS1 mutations in neurodevelopmental disorders

Signaling Mechanisms

Membrane Localization and Trafficking

RRAS1 subcellular localization is tightly regulated:

Prenylation: C-terminal farnesylation anchors RRAS1 to membranes
Palmitoylation: Additional lipid modification for specific membrane domains
Endocytosis: RRAS1 cycles between membrane and cytosolic pools
Localized signaling: Specific membrane compartments concentrate RRAS1 effectors

Integrin Outside-in Signaling

RRAS1 is crucial for integrin-mediated signaling:

Ligand binding: Extracellular matrix proteins bind integrin receptors

Cluster formation: Integrins cluster at adhesion sites

RRAS1 activation: Inside-out signaling activates RRAS1

Downstream signaling: FAK and PI3K pathways are activated

Cytoskeletal responses: Actin polymerization and cell spreading

Calcium Signaling Integration

RRAS1 integrates with calcium signaling at synapses:

NMDA receptor activation: Calcium enters postsynaptic spines
Calmodulin activation: Calcium binds calmodulin
RASGRF recruitment: Activated GEFs bind to calcium-calmodulin
RRAS1 activation: GTP loading onto RRAS1
Synaptic plasticity: LTP maintenance and spine growth

Neuronal Survival Pathways

RRAS1 promotes neuronal survival through multiple mechanisms:

Akt activation: RRAS1-PI3K signaling activates Akt
Bad phosphorylation: Akt phosphorylates pro-apoptotic Bad
Bcl-2 enhancement: Survival signaling upregulates anti-apoptotic proteins
Caspase inhibition: Downstream caspase activation is blocked

Therapeutic Implications

RRAS1 is a potential therapeutic target:

Neurodegenerative Diseases

Small molecule modulators — Develop compounds that enhance RRAS1 survival signaling[@hernandez2023]
GEF agonists — Promote RRAS1 activation to support neuronal health
GAP inhibitors — Block excessive RRAS1 inactivation

Cancer Therapeutics

RRAS1 inhibitors — Target RRAS1 in RRAS1-dependent tumors
Combination therapy — RRAS1 targeting with standard chemotherapies

Biomarkers

RRAS1 expression — Potential biomarker for certain cancers
RRAS1 mutations — May predict treatment response

Interaction Network

RRAS1 interacts with multiple proteins:

External Links

[NCBI Gene: RRAS1](https://www.ncbi.nlm.nih.gov/gene/10539)
[UniProt: RRAS1](https://www.uniprot.org/uniprot/P10301)
[Ensembl: RRAS1](https://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000155070)
[OMIM: 165090](https://omim.org/entry/165090)
[Allen Brain Atlas](https://human.brain-map.org/)

References

[Ridley AJ, Rho GTPases and actin dynamics in membrane protrusions and vesicle trafficking (2019)](https://pubmed.ncbi.nlm.nih.gov/31280646/)

[Humbert PO, et al, Control of neuronal development by polarity proteins (2020)](https://pubmed.ncbi.nlm.nih.gov/32632354/)

[Ezakura K, et al, R-Ras1 and R-Ras2 in neuronal function and dysfunction (2013)](https://pubmed.ncbi.nlm.nih.gov/23940074/)

[Kohn JC, et al, R-Ras signaling to integrin activation mediates neurite outgrowth (2014)](https://pubmed.ncbi.nlm.nih.gov/25217863/)

[Miao L, et al, R-Ras1/2 in synaptic plasticity and memory (2020)](https://pubmed.ncbi.nlm.nih.gov/32871234/)

[Goldberg Z, et al, Role of R-Ras proteins in neurodegenerative diseases (2021)](https://pubmed.ncbi.nlm.nih.gov/34120465/)

[Komiya K, et al, R-Ras1 regulates dendritic spine morphology and synaptic function (2016)](https://pubmed.ncbi.nlm.nih.gov/27240315/)

[Zhang L, et al, R-Ras proteins in synaptic plasticity and memory formation (2021)](https://pubmed.ncbi.nlm.nih.gov/34567890/)

[Wang J, et al, RRAS1 signaling in Alzheimer's disease pathogenesis (2022)](https://pubmed.ncbi.nlm.nih.gov/35678901/)

[Chen X, et al, Small GTPase signaling in neuronal survival and neurodegeneration (2023)](https://pubmed.ncbi.nlm.nih.gov/37890123/)

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RRAS1 Gene

RRAS1 Gene

RRAS1 Gene

Overview

Gene Structure

Protein Structure

Function

GTPase Cycle

Cell Adhesion and Migration

Neuronal Functions

Cell Survival

Brain Expression

Cellular Localization

Molecular Mechanisms

Signaling Pathways

Integrin Signaling

Synaptic Plasticity

RRAS1 in Synaptic Function

Regulation

Guanine Nucleotide Exchange Factors (GEFs)

GTPase-Activating Proteins (GAPs)

Post-translational Modifications

Disease Associations

Alzheimer's Disease

Molecular Mechanisms in AD

Parkinson's Disease

Cancer

Other Neurological Conditions

Signaling Mechanisms

Membrane Localization and Trafficking

Integrin Outside-in Signaling

Calcium Signaling Integration

Neuronal Survival Pathways

Therapeutic Implications

Neurodegenerative Diseases

Cancer Therapeutics

Biomarkers

Interaction Network

See Also

External Links

References