Affinage

MRAS

Ras-related protein M-Ras · UniProt O14807

Length
208 aa
Mass
23.8 kDa
Annotated
2026-06-10
75 papers in source corpus 28 papers cited in narrative 28 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

MRAS (M-Ras/R-Ras3) is a plasma-membrane-associated small GTPase of the RAS family that cycles between GDP- and GTP-bound states and, in its active form, drives MAPK pathway activation through a non-canonical mechanism distinct from direct RAS–RAF engagement (PMID:16630891, PMID:9395237). Its defining role is as the GTP-dependent targeting and regulatory subunit of the SHOC2–MRAS–PP1C heterotrimeric holophosphatase, in which SHOC2 bridges MRAS and the PP1C catalytic subunit through its concave leucine-rich-repeat surface and a cryptic N-terminal RVXF motif, with stable ternary assembly occurring only when MRAS is GTP-loaded (PMID:35831509, PMID:35830882, PMID:36175670). This holophosphatase selectively dephosphorylates the inhibitory S259/S365 site on RAF kinases to relieve RAF autoinhibition and promote ERK signaling, and efficient RAF dephosphorylation requires MRAS membrane localization (PMID:16630891, PMID:30348783). The complex is tuned by competing regulators: SCRIB acts as an antagonistic PP1 regulatory subunit competing with SHOC2, and GNG2 inhibits MRAS-dependent ERK/AKT signaling (PMID:24211266, PMID:35322009). Beyond RAF, MRAS-GTP couples to Rap1/Rap2 activation via the RA-domain GEF RA-GEF-2, a plasma-membrane axis that mediates TNF-α-triggered LFA-1 integrin activation (PMID:11524421, PMID:17538012), and engages the effector Lamellipodin downstream of Plexin-B1 GAP activity to control actin-based dendritic remodeling in cortical neurons (PMID:19444311, PMID:22699910). MRAS supports cell-type-specific differentiation programs, signaling through B-Raf to sustain ERK/CREB during NGF-driven neuritogenesis and through PI3K-Akt for survival (PMID:12138204, PMID:16923128, PMID:10803462), and contributes to collective cell migration by recruiting SHOC2 to junctions to phosphoregulate p120-catenin/E-cadherin turnover (PMID:30808747). Activating MRAS mutations that impair GTPase activity and enhance SHOC2–PP1C complex formation cause Noonan syndrome with elevated MAPK and PI3K-AKT signaling (PMID:28289718, PMID:31108500), and YAP-driven transcriptional upregulation of MRAS underlies adaptive resistance to KRAS G12C inhibitors (PMID:37277529).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 1997 High

    Established MRAS as a bona fide small GTPase with intrinsic GDP/GTP binding and hydrolysis, defining the GTPase cycle and a constitutively active mutant that reshapes the actin cytoskeleton.

    Evidence recombinant protein GTPase assays, mutagenesis, and cytoskeletal phenotyping in fibroblasts

    PMID:9395237

    Open questions at the time
    • Effectors mediating actin remodeling not identified
    • No physiological upstream signal defined
  2. 2000 High

    Defined MRAS regulatory inputs, showing it shares GEFs (Sos, RasGRF, CalDAG-GEFs) and GAPs (p120 GAP, NF-1) with classical Ras rather than R-Ras, placing it in the canonical Ras regulatory regime.

    Evidence in vitro nucleotide exchange and GTPase assays plus in vivo GTP-loading in 293T cells

    PMID:10777492

    Open questions at the time
    • Receptor-level signals coupling to these GEFs not resolved
    • GAP specificity in physiological contexts untested
  3. 2000 Medium

    Identified the first GTP-dependent effectors, linking MRAS to Rap1 GEFs (MR-GEF) and to PI3K-Akt survival signaling, expanding MRAS output beyond the cytoskeleton.

    Evidence GST pulldowns, co-IP, Rap1 GEF reporter assays, and PI3K lipid kinase assays with pharmacological inhibition

    PMID:10803462 PMID:10934204

    Open questions at the time
    • MR-GEF sequestration model relies on overexpression
    • Direct PI3K subunit binding not mapped
  4. 2001 Medium

    Extended MRAS-GTP effector repertoire to RA-GEF-2 (Rap1/Rap2 activation at the plasma membrane) and to RPM/RGL3, a negative regulator of Ras-driven Elk-1 transcription.

    Evidence GST pulldowns, colocalization imaging, Rap1 GTP-loading and Elk-1 reporter assays

    PMID:11313946 PMID:11524421

    Open questions at the time
    • RPM/RGL3 mechanism of transcriptional inhibition unresolved
    • Single-lab effector specificity claims
  5. 2002 High

    Demonstrated cell-type-specific RAF coupling, with MRAS binding and stimulating B-Raf (not c-Raf) to drive MAPK-dependent neuronal differentiation in PC12 cells.

    Evidence Raf-binding and kinase assays, dominant-negative epistasis, and neurite outgrowth quantification

    PMID:12138204

    Open questions at the time
    • Basis for B-Raf selectivity not structurally defined
    • Restricted to PC12 context
  6. 2006 High

    Resolved the non-canonical mechanism of MAPK activation: GTP-MRAS recruits the SHOC2–PP1C phosphatase to dephosphorylate the inhibitory RAF S259 site, establishing MRAS as an effector scaffold essential for growth-factor MAPK signaling, while NGF-induced sustained MRAS activation sustains ERK/CREB for neuritogenesis.

    Evidence proteomics identification, biochemical reconstitution, phosphatase and MAPK assays, plus siRNA/dominant-negative epistasis in PC12 cells

    PMID:16630891 PMID:16923128

    Open questions at the time
    • Stoichiometry and assembly order not yet defined
    • PP1C substrate specificity determinants unknown
  7. 2013 High

    Revealed combinatorial regulation of the holophosphatase by SCRIB, a competing PP1 regulatory subunit, and tied SHOC2/MRAS function to malignant properties of RAS-mutant tumor cells and polarized migration.

    Evidence reciprocal co-IP, biochemical competition assays, and shRNA depletion with migration/transformation readouts

    PMID:24211266

    Open questions at the time
    • Quantitative balance of SCRIB vs SHOC2 occupancy in vivo unclear
  8. 2013 Medium

    Implicated MRAS in developmental cell-fate control, required for proper OCT4/NANOG downregulation in ES cell differentiation and modulating FGF/activin responsiveness in Xenopus.

    Evidence shRNA knockdown in mESCs and Xenopus gain/loss-of-function with in situ hybridization

    PMID:23863483

    Open questions at the time
    • Effector pathway linking MRAS to pluripotency gene control not defined
    • Single lab
  9. 2018 High

    Formalized MRAS as a dual PP1 regulatory/targeting subunit with strict S259/S365 substrate specificity, and showed Noonan mutations across all three subunits converge on enhanced ternary complex formation.

    Evidence biochemical reconstitution, switch-region and membrane-localization mutagenesis, and cell-based ERK assays

    PMID:30348783

    Open questions at the time
    • Atomic architecture not yet visualized at this point
    • SHOC2/PP2A-A convergence inferred from prediction
  10. 2019 High

    Connected MRAS–SHOC2 signaling to junctional remodeling, showing the complex phosphoregulates p120-catenin/E-cadherin to enable junction turnover during collective migration, with Noonan-associated gain-of-function causing zebrafish gastrulation defects.

    Evidence dominant-inhibitory and shRNA/rescue experiments, live-cell junction imaging, co-IP, and zebrafish gastrulation assays

    PMID:30808747

    Open questions at the time
    • Direct phosphatase substrate at the junction not pinpointed
  11. 2022 High

    Determined the atomic architecture of the SHOC2–MRAS–PP1C holophosphatase, showing SHOC2 bridges GTP-MRAS and PP1C via its LRR concave surface and a cryptic RVXF motif, with ordered assembly and disease mutations at interfaces enhancing complex formation.

    Evidence cryo-EM and two independent crystal structures with deep mutational scanning, biophysical binding, and phosphatase assays

    PMID:35830882 PMID:35831509 PMID:36175670

    Open questions at the time
    • RAF substrate engagement by the holophosphatase not captured structurally
    • Dynamics of membrane-anchored assembly not resolved
  12. 2023 High

    Identified YAP-driven transcriptional induction of MRAS as a feedback resistance mechanism to KRAS G12C inhibitors, with induced MRAS forming the SHOC2 complex to reactivate MAPK signaling.

    Evidence ChIP/reporter validation of YAP–MRAS, MRAS knockdown/overexpression, MRAS–SHOC2 co-IP, and in vivo tumor models

    PMID:37277529

    Open questions at the time
    • Generality across KRAS-driven tumor types not established
  13. 2024 Medium

    Provided the inactive GDP-bound conformational reference for MRAS, revealing switch-region differences from active and predicted structures to guide selective inhibitor design.

    Evidence X-ray crystallography of GDP-bound M-RAS in two crystal forms

    PMID:39196705

    Open questions at the time
    • No functional mutagenesis validation
    • No co-structure with inhibitor

Open questions

Synthesis pass · forward-looking unresolved questions
  • How MRAS effector choice (SHOC2-PP1C/RAF vs RA-GEF-2/Rap1 vs Lamellipodin vs PI3K) is partitioned across cell types and membrane microdomains, and how the holophosphatase physically engages RAF, remain unresolved.
  • No structure of the holophosphatase bound to RAF substrate
  • Determinants of effector selection in vivo undefined
  • Physiological GEF/GAP signals at native receptors incompletely mapped

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003924 GTPase activity 4 GO:0060090 molecular adaptor activity 4 GO:0060089 molecular transducer activity 3 GO:0098772 molecular function regulator activity 3
Localization
GO:0005886 plasma membrane 5
Pathway
R-HSA-162582 Signal Transduction 4 R-HSA-1266738 Developmental Biology 3 R-HSA-1643685 Disease 3 R-HSA-168256 Immune System 2
Partners
AF6GNG2PLEXIN-B1PPP1CBRA-GEF-2RGL3SCRIBSHOC2
Complex memberships
SHOC2–MRAS–PP1C holophosphatase

Evidence

Reading pass · 28 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2006 M-Ras functions as a specific effector scaffold: GTP-bound M-Ras recruits the Shoc2/Sur-8–PP1c phosphatase holoenzyme to dephosphorylate the inhibitory S259 site on Raf kinases, thereby stimulating Raf activity. This represents a distinct mechanism from classical Ras–Raf interaction and is essential for MAPK pathway activation by growth factors. Proteomics/mass spectrometry identification of complex; biochemical reconstitution; phosphatase activity assays; shRNA knockdown with MAPK pathway readout Molecular cell High 16630891
2022 Cryo-EM structure of the SHOC2–MRAS–PP1C heterotrimeric holophosphatase complex reveals that SHOC2 bridges PP1C and GTP-loaded MRAS through its concave leucine-rich repeat surface; complex assembly is ordered (SHOC2–PP1C first, then MRAS-GTP stabilizes); an N-terminal cryptic RVXF motif in SHOC2 further engages PP1C. RASopathy and cancer mutations reside at subunit interfaces and enhance complex formation. Cryo-electron microscopy; deep mutational scanning of SHOC2; biophysical binding assays; mutagenesis Nature High 35831509
2022 X-ray crystal structure of the MRAS–SHOC2–PP1C ternary complex shows all three subunits engage in synergistic, reciprocal contacts; complex forms only when MRAS is GTP-bound; SHOC2 acts as scaffolding protein bringing PP1C and MRAS together; dephosphorylation of RAF substrates by PP1C is enhanced upon SHOC2–MRAS interaction; other RAS isoforms can substitute for MRAS in a cooperative, GTP-dependent manner. X-ray crystallography; biophysical affinity measurements; phosphatase activity assays; mutagenesis Nature High 35830882
2022 High-resolution crystal structure of the SHOC2–MRAS–PP1C complex and apo-SHOC2 confirms that SHOC2 functions as a scaffolding protein, requires MRAS in its active (GTP-bound) state for stable ternary complex formation, and that Noonan syndrome mutations enhance complex formation and RAF dephosphorylation activity. X-ray crystallography; biochemical phosphatase assays; mutagenesis Nature structural & molecular biology High 36175670
2018 MRAS and SHOC2 serve as dual PP1 regulatory subunits in the SHOC2–MRAS–PP1C holoenzyme with striking substrate specificity for the S259/S365 inhibitory site on RAF. Membrane localization of MRAS (targeting subunit function) is required for efficient RAF dephosphorylation in cells. SHOC2 predicted structure resembles the PP2A A-subunit, suggesting convergent evolution. Noonan syndrome mutations in MRAS, SHOC2, or PPP1CB invariably enhance ternary complex formation. Biochemical reconstitution; mutagenesis of MRAS switch I and interswitch regions; cell-based ERK pathway assays; membrane-localization mutants; structural prediction Proceedings of the National Academy of Sciences of the United States of America High 30348783
2013 MRAS, SHOC2, and the polarity protein SCRIB form a macromolecular complex. SCRIB acts as a PP1 regulatory subunit that competes with SHOC2 for PP1 molecules within the same complex, antagonizing SHOC2-mediated RAF dephosphorylation. SHOC2 function is selectively required for malignant properties of RAS-mutant tumor cells. Both MRAS and SHOC2 are required for polarized cell migration. Co-immunoprecipitation; biochemical competition assays; shRNA depletion with cell migration and transformation readouts Molecular cell High 24211266
2000 GEF specificity for M-Ras: mSos, RasGRF, CalDAG-GEFII, and CalDAG-GEFIII promote guanine nucleotide exchange on M-Ras in cells and in vitro. GAPs Gap1(m), p120 GAP, and NF-1 stimulate M-Ras GTPase activity, whereas R-Ras GAP does not. These regulatory interactions resemble those of classical Ras rather than R-Ras. In vitro nucleotide exchange assays; in vivo GTP-loading assays in 293T cells; GTPase activity assays The Journal of biological chemistry High 10777492
2000 MR-GEF (a Rap1 GEF) binds specifically to GTP-loaded M-Ras via its RA domain both in vitro and by co-immunoprecipitation in vivo. Constitutively active M-Ras(71L) inhibits MR-GEF-stimulated Rap1A activation in a dose-dependent manner, indicating M-Ras negatively regulates Rap1 through sequestration of MR-GEF. GST pulldown in vitro binding; co-immunoprecipitation; Rap1 GEF reporter assay The Journal of biological chemistry Medium 10934204
2001 RA-GEF-2, a Rap1/Rap2 GEF, binds M-Ras-GTP specifically through its RA domain (not other Ras family members tested). In COS-7 cells, RA-GEF-2 colocalizes with activated M-Ras at the plasma membrane and elevates GTP-bound Rap1 at the plasma membrane when co-expressed with active M-Ras. Thus M-Ras signals to Rap1/Rap2 via RA-GEF-2 specifically at the plasma membrane. GST pulldown; fluorescence colocalization; Rap1 activity assays (GTP-loading) The Journal of biological chemistry Medium 11524421
2007 The M-Ras–RA-GEF-2–Rap1 signaling axis mediates TNF-α-triggered LFA-1 integrin activation in hematopoietic cells. TNF-α activates M-Ras and Rap1 at the plasma membrane, recruits RA-GEF-2 there, and this pathway is required for LFA-1-mediated cell aggregation; knockdown of RA-GEF-2 or Rap1 abrogates M-Ras-driven LFA-1 activation. Validated in RA-GEF-2-deficient mice splenocytes. shRNA knockdown; overexpression; LFA-1 cell aggregation assays; Rap1 GTP-loading assay; RA-GEF-2 knockout mouse Molecular biology of the cell High 17538012
1999 M-Ras co-immunoprecipitates with AF6 (a cell junction regulator) in a GTP-dependent manner; it interacts only weakly with Raf-1, A-Raf, B-Raf, PI3Kδ, RalGDS, and Rin1 in yeast two-hybrid assay. M-Ras GTP/GDP cycle is regulated by Sos1, GRF1 (GEFs), and p120 Ras GAP. Co-immunoprecipitation; yeast two-hybrid; in vivo GTP-loading assay The Journal of biological chemistry Medium 10446149
2009 Plexin-B1 functions as a GAP for M-Ras (in addition to R-Ras). In cortical neurons, M-Ras expression increases during dendritic development; M-Ras knockdown reduces dendritic outgrowth and branching while constitutively active M-Ras(Q71L) enhances it. Sema4D stimulation suppresses M-Ras activity via Plexin-B1 GAP activity, and this suppression is blocked by M-Ras(Q71L). M-Ras(Q71L) drives ERK activation to promote dendrite growth; Sema4D suppresses ERK. GAP activity assay; siRNA knockdown; overexpression of constitutively active mutant; ERK activation assays; dendritic morphology quantification in cortical neurons EMBO reports High 19444311
2012 Downstream of M-Ras in dendrites, Lamellipodin (Lpd) is an effector that undergoes M-Ras-dependent membrane translocation; this translocation is suppressed by Sema4D. Lpd is required for basal and M-Ras-mediated dendritic development, and its Ena/VASP-binding region is required for dendrite development. Membrane targeting of the Lpd Ena/VASP domain is sufficient to overcome Sema4D-mediated dendritic reduction. In utero electroporation validated this M-Ras–Lpd axis in cortical dendrite development in vivo. Subcellular fractionation; co-immunoprecipitation; siRNA knockdown; constitutively active M-Ras overexpression; in utero electroporation in vivo The Journal of neuroscience High 22699910
2002 R-Ras3/M-Ras is activated by NGF and bFGF but not EGF in PC12 cells. In PC12 cells (but not NIH 3T3 cells), M-Ras activates MAPK by binding and stimulating B-Raf specifically (not c-Raf), explaining cell-type-specific neuronal differentiation. Dominant-negative M-Ras attenuates NGF- and GRP-induced PC12 differentiation. Ras activity assays; Raf kinase binding assays; dominant-negative overexpression; MAPK activation assays; neurite outgrowth quantification Molecular and cellular biology High 12138204
2006 NGF induces sustained (not transient) activation of M-Ras in PC12 cells, which sustains ERK pathway activation and CREB phosphorylation, leading to neurite outgrowth. Knockdown of endogenous M-Ras or dominant-negative M-Ras blocks NGF-induced neuritogenesis. MEK inhibitors prevent M-Ras-induced neurite outgrowth. Dominant-negative CREB blocks M-Ras-induced neuritogenesis. siRNA knockdown; dominant-negative overexpression; constitutively active mutant overexpression; ERK/CREB phosphorylation assays; neurite morphology quantification Genes to cells High 16923128
2000 R-Ras3/M-Ras activates Akt/PKB in a PI3K-dependent manner; M-Ras-GTP affinity-precipitates PI3K from cell extracts and associated lipid kinase activity is detectable. PI3K inhibitors (Wortmannin, LY294002) and dominant-negative PI3K block R-Ras3-induced Akt activation. This PI3K–Akt pathway mediates M-Ras-induced cell survival in PC12 cells. Co-immunoprecipitation/affinity precipitation; PI3K lipid kinase assay; pharmacological inhibition; cell survival assay Oncogene Medium 10803462
2001 RPM/RGL3 (a RalGDS-family member) binds strongly and selectively to GTP-bound M-Ras and p21 Ras. Unlike Rlf, RPM/RGL3 does not activate Elk-1 reporter gene but strongly inhibits Elk-1 induction by activated H-Ras or MEKK-1. The inhibitory effect requires a second signal from p21 Ras/MEKK-1 but not Raf-1 or M-Ras. RPM/RGL3 overexpression inhibits growth of Src-transformed fibroblasts. GST pulldown; yeast two-hybrid; Elk-1 reporter gene assay; cell growth assay Oncogene Medium 11313946
1997 M-Ras is a novel small GTPase with GDP/GTP binding and GTPase activities demonstrated with bacterially expressed recombinant protein. The G22V mutant is constitutively active (unable to hydrolyze GTP). M-Ras localizes to plasma membrane-associated structures. Constitutively active M-Ras(G22V) induces peripheral microspikes and actin foci formation, causes loss of stress fibers, and produces dendritic cell morphology in fibroblasts. Recombinant protein GTP binding and GTPase assay; mutagenesis; epitope-tag localization; microinjection; transfection with actin cytoskeleton readout Oncogene High 9395237
2009 M-Ras is induced and activated by BMP-2 in mesenchymal and myoblast cells. Constitutively active M-Ras(G22V) promotes osteoblast differentiation and transdifferentiation of C2C12 myoblasts to osteoblasts. M-Ras RNAi knockdown inhibits osteoblast differentiation. BMP-2-induced osteoblastic transdifferentiation by M-Ras requires p38 MAPK and JNK, but not MEK/ERK or PI3K. RNAi knockdown; stable overexpression of constitutively active mutant; osteoblast differentiation markers; pharmacological inhibitors of p38, JNK, MEK, PI3K Experimental cell research Medium 19800879
2019 Activated M-Ras recruits SHOC2 to cell-surface junctions where M-Ras/SHOC2 signaling modulates E-cadherin/p120-catenin interaction and junctional E-cadherin expression via phosphoregulation of p120-catenin and downstream ERK activation, thereby enabling E-cadherin junction turnover required for collective cell migration. Loss of M-Ras (dominant-inhibitory S27N) or SHOC2 depletion reduces junction turnover and collective migration. Noonan syndrome Myr-Shoc2 mutant causes gain-of-function with increased junction turnover and faster but less cohesive migration; this induces gastrulation defects in zebrafish. Dominant-inhibitory overexpression; shRNA depletion/reconstitution; live-cell imaging of junction dynamics; co-immunoprecipitation of E-cadherin/p120-catenin; Western blot for p120-catenin phosphorylation; zebrafish gastrulation assay Proceedings of the National Academy of Sciences of the United States of America High 30808747
2023 YAP directly transcriptionally induces MRAS expression following KRAS G12C inhibitor treatment. KRAS G12C inhibitor-induced Scribble mis-localization suppresses Hippo-YAP signaling, causing YAP nuclear translocation and MRAS upregulation. Induced MRAS forms a complex with SHOC2 and activates MAPK signaling as a feedback resistance mechanism. Abrogation of YAP activation or MRAS induction enhances KRAS G12C inhibitor efficacy in vivo. ChIP/reporter assay for direct YAP target validation; MRAS overexpression and knockdown; Co-IP of MRAS–SHOC2 complex; in vivo tumor models with inhibitor treatment Nature cancer High 37277529
2017 The Noonan syndrome p.Gly23Val-MRAS variant shows ~40-fold increased GTP-loading (constitutive activation) due to impaired GTPase activity. Expression of this mutant causes enhanced MAPK and PI3K-AKT pathway activation in cells. GTP-loading assay; molecular dynamics simulation; ectopic expression with pathway signaling readout (Western blot for pERK, pAKT) JCI insight Medium 28289718
2020 Noonan syndrome MRAS mutants (p.Thr68Ile, p.Gly23Arg) exhibit impaired GTPase activity leading to constitutive GTP-bound state, constitutive plasma membrane targeting, prolonged localization in non-raft microdomains, enhanced binding to PPP1CB and SHOC2, and variably increased MAPK and PI3K-AKT activation. GTPase activity assay; subcellular fractionation; co-immunoprecipitation; flow cytometry; pERK/pAKT Western blot Human molecular genetics Medium 31108500
2013 MRAS knockdown in mouse embryonic stem cells reduces expression of specific pluripotency master genes and MRAS is required for proper downregulation of OCT4 and NANOG upon differentiation. In Xenopus, MRAS modulates early cell fate decisions and neurogenesis; Mras overexpression sustains FGF and activin responsiveness in gastrula cells. Stable shRNA knockdown in mESCs; Western blot for OCT4/NANOG; Xenopus gain/loss-of-function; in situ hybridization Development (Cambridge, England) Medium 23863483
2018 M-Ras localizes transiently and in a GTP-dependent manner to phagocytic cups during FcγR-mediated phagocytosis in macrophages. GDP-locked M-Ras(S27N) significantly inhibits phagosome formation, while wild-type or GTP-locked M-Ras(G22V) facilitates IgG-opsonized erythrocyte uptake. Live-cell fluorescence imaging; ratiometric image analysis; mutant overexpression with phagocytosis quantification Microscopy (Oxford, England) Medium 29340604
1999 Constitutively active M-Ras(G22V) expressed in an IL-3-dependent hematopoietic cell line confers factor-independent growth, activates the c-fos promoter, and weakly binds Raf-1 and RalGDS Ras-binding domains. A membrane-anchoring-deficient M-Ras(G22V) mutant partially inhibits N-Ras-mediated c-fos activation, suggesting shared membrane-dependent effectors. The dominant-negative M-Ras(S27N) inhibits Src-induced c-fos activation, indicating shared GEFs with classical Ras. Retroviral transduction; factor-independent growth assay; c-fos reporter assay; GST–RBD pulldown Blood Medium 10498616
2024 Crystal structure of GDP-bound human M-RAS in two crystal forms reveals that the inactive state switch regions differ from those in active (GTP-bound) M-RAS and from the AlphaFold2-predicted structure, while the core aligns well with the predicted structure. The structure provides the inactive conformation reference for selective compound design. X-ray crystallography Acta crystallographica. Section F, Structural biology communications Medium 39196705
2022 GNG2 (G-protein gamma subunit 2) co-localizes with MRAS at the cell membrane and directly interacts with MRAS as demonstrated by FRET. GNG2 inhibits ERK and Akt activity in breast cancer cells in an MRAS-dependent manner. Fluorescence resonance energy transfer (FRET); colocalization imaging; GNG2 overexpression with MRAS dependency (knockdown control); pERK/pAKT Western blot Cell death & disease Medium 35322009

Source papers

Stage 0 corpus · 75 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2006 A phosphatase holoenzyme comprised of Shoc2/Sur8 and the catalytic subunit of PP1 functions as an M-Ras effector to modulate Raf activity. Molecular cell 178 16630891
2000 Regulatory proteins of R-Ras, TC21/R-Ras2, and M-Ras/R-Ras3. The Journal of biological chemistry 136 10777492
2000 Identification of guanine nucleotide exchange factors (GEFs) for the Rap1 GTPase. Regulation of MR-GEF by M-Ras-GTP interaction. The Journal of biological chemistry 132 10934204
1999 M-Ras/R-Ras3, a transforming ras protein regulated by Sos1, GRF1, and p120 Ras GTPase-activating protein, interacts with the putative Ras effector AF6. The Journal of biological chemistry 102 10446149
2013 An MRAS, SHOC2, and SCRIB complex coordinates ERK pathway activation with polarity and tumorigenic growth. Molecular cell 96 24211266
2001 Identification and characterization of RA-GEF-2, a Rap guanine nucleotide exchange factor that serves as a downstream target of M-Ras. The Journal of biological chemistry 80 11524421
2023 Scribble mis-localization induces adaptive resistance to KRAS G12C inhibitors through feedback activation of MAPK signaling mediated by YAP-induced MRAS. Nature cancer 76 37277529
2009 Plexin-B1 is a GTPase activating protein for M-Ras, remodelling dendrite morphology. EMBO reports 75 19444311
1997 Novel small GTPase M-Ras participates in reorganization of actin cytoskeleton. Oncogene 75 9395237
2018 SHOC2-MRAS-PP1 complex positively regulates RAF activity and contributes to Noonan syndrome pathogenesis. Proceedings of the National Academy of Sciences of the United States of America 72 30348783
2017 Elucidation of MRAS-mediated Noonan syndrome with cardiac hypertrophy. JCI insight 71 28289718
1997 Identification and characterization of R-ras3: a novel member of the RAS gene family with a non-ubiquitous pattern of tissue distribution. Oncogene 70 9400994
2022 Structure-function analysis of the SHOC2-MRAS-PP1C holophosphatase complex. Nature 65 35831509
2006 Sustained activation of M-Ras induced by nerve growth factor is essential for neuronal differentiation of PC12 cells. Genes to cells : devoted to molecular & cellular mechanisms 50 16923128
2019 MRAs in Elderly HF Patients: Individual Patient-Data Meta-Analysis of RALES, EMPHASIS-HF, and TOPCAT. JACC. Heart failure 48 31779922
2012 Semaphorin 4D/Plexin-B1-mediated M-Ras GAP activity regulates actin-based dendrite remodeling through Lamellipodin. The Journal of neuroscience : the official journal of the Society for Neuroscience 47 22699910
2002 R-Ras3/M-Ras induces neuronal differentiation of PC12 cells through cell-type-specific activation of the mitogen-activated protein kinase cascade. Molecular and cellular biology 46 12138204
1999 M-Ras, a widely expressed 29-kD homologue of p21 Ras: expression of a constitutively active mutant results in factor-independent growth of an interleukin-3-dependent cell line. Blood 46 10498616
2000 R-Ras3, a brain-specific Ras-related protein, activates Akt and promotes cell survival in PC12 cells. Oncogene 45 10803462
2007 The M-Ras-RA-GEF-2-Rap1 pathway mediates tumor necrosis factor-alpha dependent regulation of integrin activation in splenocytes. Molecular biology of the cell 44 17538012
2018 MRAS: A Close but Understudied Member of the RAS Family. Cold Spring Harbor perspectives in medicine 43 29311130
2022 Structure of the MRAS-SHOC2-PP1C phosphatase complex. Nature 42 35830882
2022 Structure of the SHOC2-MRAS-PP1C complex provides insights into RAF activation and Noonan syndrome. Nature structural & molecular biology 42 36175670
2020 Activating MRAS mutations cause Noonan syndrome associated with hypertrophic cardiomyopathy. Human molecular genetics 39 31108500
2019 Genome-wide association reveals contribution of MRAS to painful temporomandibular disorder in males. Pain 35 30431558
2004 Expression of activated M-Ras in a murine mammary epithelial cell line induces epithelial-mesenchymal transition and tumorigenesis. Oncogene 35 14961075
1999 Interleukin-9-induced expression of M-Ras/R-Ras3 oncogene in T-helper clones. Blood 34 10477695
2001 A novel potential effector of M-Ras and p21 Ras negatively regulates p21 Ras-mediated gene induction and cell growth. Oncogene 32 11313946
2009 M-Ras is activated by bone morphogenetic protein-2 and participates in osteoblastic determination, differentiation, and transdifferentiation. Experimental cell research 30 19800879
2019 M-Ras/Shoc2 signaling modulates E-cadherin turnover and cell-cell adhesion during collective cell migration. Proceedings of the National Academy of Sciences of the United States of America 28 30808747
2023 Probing mutation-induced conformational transformation of the GTP/M-RAS complex through Gaussian accelerated molecular dynamics simulations. Journal of enzyme inhibition and medicinal chemistry 24 37057639
2022 GNG2 acts as a tumor suppressor in breast cancer through stimulating MRAS signaling. Cell death & disease 24 35322009
2006 R-Ras3/(M-Ras) is involved in thermal adaptation in the critical period of thermal control establishment. Journal of neurobiology 24 16215997
2006 Characterization of R-ras3/m-ras null mice reveals a potential role in trophic factor signaling. Molecular and cellular biology 22 16980617
2019 Severe Noonan syndrome phenotype associated with a germline Q71R MRAS variant: a recurrent substitution in RAS homologs in various cancers. American journal of medical genetics. Part A 19 31173466
2005 Expression of a constitutively active mutant of M-Ras in normal bone marrow is sufficient for induction of a malignant mastocytosis/mast cell leukemia, distinct from the histiocytosis/monocytic leukemia induced by expression of activated H-Ras. Oncogene 17 15735740
2019 MRAS Variants Cause Cardiomyocyte Hypertrophy in Patient-Specific Induced Pluripotent Stem Cell-Derived Cardiomyocytes: Additional Evidence for MRAS as a Definitive Noonan Syndrome-Susceptibility Gene. Circulation. Genomic and precision medicine 16 31638832
2023 Steroidal or non-steroidal MRAs: should we still enable RAASi use through K binders? Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association 15 36264349
2016 The safety of mineralocorticoid receptor antagonists (MRAs) in patients with heart failure. Expert opinion on drug safety 14 26958701
2008 M-Ras evolved independently of R-Ras and its neural function is conserved between mammalian and ascidian, which lacks classical Ras. Gene 14 18977283
2006 Expression of activated M-Ras in hemopoietic stem cells initiates leukemogenic transformation, immortalization and preferential generation of mast cells. Oncogene 14 16501601
2013 MRAS GTPase is a novel stemness marker that impacts mouse embryonic stem cell plasticity and Xenopus embryonic cell fate. Development (Cambridge, England) 13 23863483
2012 The role of mineralocorticoid receptor antagonists (MRAs) in very old patients with heart failure. Heart failure reviews 13 21996778
2020 M-Ras is Muscle-Ras, Moderate-Ras, Mineral-Ras, Migration-Ras, and Many More-Ras. Experimental cell research 11 33130177
2005 Distribution of actin filaments, non-muscle myosin, M-Ras, and extracellular signal-regulated kinase (ERK) in osteoclasts after calcitonin administration. Archives of histology and cytology 11 16079460
2004 Multiple aspects of the phenotype of mammary epithelial cells transformed by expression of activated M-Ras depend on an autocrine mechanism mediated by hepatocyte growth factor/scatter factor. Molecular cancer research : MCR 10 15140946
2021 Atypical, severe hypertrophic cardiomyopathy in a newborn presenting Noonan syndrome harboring a recurrent heterozygous MRAS variant. American journal of medical genetics. Part A 9 34080768
2015 Genetic insight into the role of MRAS in coronary artery disease risk. Gene 8 25800439
2015 Urinary Retention, Incontinence, and Dysregulation of Muscarinic Receptors in Male Mice Lacking Mras. PloS one 8 26516777
2013 MRAS Genetic Variation Is Associated with Atherothrombotic Stroke in the Han Chinese Population. Journal of clinical neurology (Seoul, Korea) 8 24285963
2024 Comparative efficacy and safety of SGLT2is and ns-MRAs in patients with diabetic kidney disease: a systematic review and network meta-analysis. Frontiers in endocrinology 6 39027482
2023 Structural insights into the role of SHOC2-MRAS-PP1C complex in RAF activation. The FEBS journal 6 37074066
2016 Muscle RAS oncogene homolog (MRAS) recurrent mutation in Borrmann type IV gastric cancer. Cancer medicine 6 27891760
2019 The influence of MRAS gene variants on ischemic stroke and serum lipid levels in Chinese Han population. Medicine 5 31770223
2012 Genetic and functional analyses of MRAS and HNF1A genes in diabetes and diabetic nephropathy. Folia biologica 5 22849862
2018 Transient recruitment of M-Ras GTPase to phagocytic cups in RAW264 macrophages during FcγR-mediated phagocytosis. Microscopy (Oxford, England) 4 29340604
2025 MRAS: Master Regulator Analysis of Alternative Splicing. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 3 40323145
2024 MRAS in coronary artery disease-Unchartered territory. IUBMB life 3 38251784
2023 Generation of a genetically-modified induced pluripotent stem cell line harboring a Noonan syndrome-associated gene variant MRAS p.G23V. Stem cell research 3 37141804
2017 MRAS gene marker rs9818870 is not associated with acute coronary syndrome in the Czech population and does not predict mortality in males after acute coronary syndrome. Advances in clinical and experimental medicine : official organ Wroclaw Medical University 3 29264877
2025 Sodium zirconium cyclosilicate for MRAs optimization in HFrEF: lessons learned from the REALIZE-K trial. Heart failure reviews 2 39883259
2025 M-Ras distinct activation scenarios: A mechanistic outlook and targeting. Computational and structural biotechnology journal 2 41340891
2020 Correlation between MRAS gene polymorphism and atherosclerosis. European review for medical and pharmacological sciences 2 32495899
2024 Crystal structure of the GDP-bound human M-RAS protein in two crystal forms. Acta crystallographica. Section F, Structural biology communications 1 39196705
2023 MRAs may have lost their cornerstone position for heart failure treatment in the age of SGLT-2 inhibitors: A meta-analysis of randomized controlled trials. Heart failure reviews 1 37369935
2016 Should MRAs be at the front row in heart failure? A plea for the early use of mineralocorticoid receptor antagonists in medical therapy for heart failure based on clinical experience. Heart failure reviews 1 27620301
2026 Novel characterization of MRAS mutation-associated Noonan syndrome: Mild adult-onset hypertrophic cardiomyopathy combined with infective endocarditis: A case report. Medicine 0 41517739
2026 Evolving Mineralocorticoid Receptor Antagonism: a Narrative Review on Differences between Steroidal MRAs, Non-Steroidal MRAs and Aldosterone Synthase Inhibitors in Cardiorenal Disease. Current heart failure reports 0 41615644
2026 Astragaloside IV Ameliorates Diabetic Cardiomyopathy by Suppressing the GNG2/MRAS-ERK Signaling Pathway. International journal of general medicine 0 41836115
2026 Hypertrophic Cardiomyopathy as a Key Feature of MRAS-Related Noonan Syndrome: New Case and Comprehensive Literature Review. Prenatal diagnosis 0 41866303
2025 To MRAs treatment or not? evidence from a meta-analysis of randomized controlled trials of different MRAs on cardiovascular health in heart failure. Frontiers in cardiovascular medicine 0 40771762
2025 Evidence-based validation of cardiovascular benefits from novel MRAs in type 2 diabetes: A meta-analysis of over 30,000 patients. Journal of diabetes and its complications 0 41317458
2024 Aberrant expression of MRAS and HEG1 as the biomarkers for osimertinib resistance in LUAD. Discover oncology 0 39560891
2023 In adults, MRAs reduce AF occurrence vs. non-MRAs. Annals of internal medicine 0 37782917
1988 [Population structure and the anthropogenetic traits of Shortzy in the Mras-Su River basin]. Genetika 0 3181752

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