Affinage

SHOC2

Leucine-rich repeat protein SHOC-2 · UniProt Q9UQ13

Length
582 aa
Mass
64.9 kDa
Annotated
2026-06-10
78 papers in source corpus 33 papers cited in narrative 31 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

SHOC2 is a leucine-rich repeat scaffold protein that positions RAS-family GTPases for activation of the RAF–MEK–ERK cascade, acting genetically downstream of RAS but upstream of RAF (PMID:9674433, PMID:10783161). Its central biochemical function is as the scaffolding subunit of a heterotrimeric holophosphatase formed with GTP-loaded M-RAS and the catalytic subunit of protein phosphatase 1 (PP1C); within this complex SHOC2 confers RAF substrate specificity, and the holoenzyme dephosphorylates the inhibitory S259 site on RAF kinases to relieve autoinhibition (PMID:16630891, PMID:30348783). Cryo-EM and crystal structures show that crescent-shaped SHOC2 cradles PP1C and M-RAS through its concave LRR surface and an N-terminal disordered RVXF motif, with assembly initiated by SHOC2–PP1C binding and stabilized only when M-RAS (or substituting RAS isoforms) is GTP-bound (PMID:35831509, PMID:35768504, PMID:35830882, PMID:36175670). This S259 dephosphorylation licenses growth factor-induced RAF heterodimerization and MEK release from BRAF, and SHOC2 is selectively required for the rapid transient phase of ERK activation and for ERK signaling in RAS-mutant cells under anchorage-independent conditions (PMID:30348783, PMID:31213532). SHOC2 scaffold activity is spatiotemporally controlled: EGFR/RAS-driven, clathrin-dependent translocation to Rab7 late endosomes is required for ERK activation, and a ubiquitination cycle involving HUWE1, FBXW7, the PSMC5 ATPase, and USP7 tunes SHOC2 and RAF-1 levels and signaling output (PMID:22606262, PMID:25022756, PMID:26519477, PMID:30865892, PMID:34553755). Loss of SHOC2 prevents MEK-inhibitor-induced RAF dimerization and selectively sensitizes KRAS- and EGFR-mutant tumors to MEK inhibition, while direct SHOC2–RAS(Q61) interaction makes it a druggable dependency in RAS(Q61)-mutant cancers (PMID:31182717, PMID:40335703). Gain-of-function in this scaffold underlies Noonan-like RASopathy: the S2G mutation introduces an N-myristoylation site that mistargets SHOC2 to the plasma membrane and excludes it from late endosomes, dysregulating ERK dynamics, and RASopathy mutations in SHOC2, MRAS, and PPP1CB invariably enhance ternary complex formation (PMID:19684605, PMID:22606262, PMID:30348783).

Mechanistic history

Synthesis pass · year-by-year structured walk · 16 steps
  1. 1998 High

    Established where SHOC2 acts in the RAS-MAPK pathway, placing it downstream of RAS and upstream of RAF rather than as a generic adaptor.

    Evidence Genetic epistasis in C. elegans plus in vitro RAS-isoform binding assays for the human ortholog

    PMID:9618511 PMID:9674433

    Open questions at the time
    • Did not define the biochemical activity of the complex
    • Mechanism of how SUR-8 couples RAS to RAF unresolved
    • Isoform selectivity (K/N-RAS vs H-RAS) not mechanistically explained
  2. 2000 High

    Showed SHOC2 forms a ternary complex bridging RAS and RAF simultaneously and enhances RAS/EGF-induced RAF–ERK activation, supporting a scaffold model acting between RAS and RAF.

    Evidence Reciprocal Co-IP and kinase activation assays with active RAF/MEK bypass

    PMID:10783161

    Open questions at the time
    • No enzymatic activity attributed to the complex
    • Did not identify additional subunits
  3. 2006 High

    Defined the molecular function of the complex: SHOC2–PP1C is an M-RAS effector holophosphatase that dephosphorylates the inhibitory S259 RAF site to activate MAPK.

    Evidence Mass spectrometry, in vitro phosphatase assay, and RNAi with pathway readouts

    PMID:16630891

    Open questions at the time
    • Structural basis of substrate specificity unknown
    • How PP1C is targeted specifically to RAF unresolved at the time
  4. 2009 High

    Connected SHOC2 to RASopathy disease by showing the S2G mutation creates an N-myristoylation site causing aberrant plasma membrane targeting and dysregulated MAPK activation.

    Evidence N-myristoylation assay, subcellular localization, mutant expression in cells and C. elegans

    PMID:19684605

    Open questions at the time
    • Did not establish the normal localization signal mislocalized by S2G
    • Cell-type specificity of MAPK enhancement not mechanistically explained
  5. 2010 High

    Provided kinetic and signaling-integration detail: SHOC2 accelerates RAS–RAF association/dissociation and integrates Ca2+/calmodulin inputs at RAF1.

    Evidence Live-cell FRET biosensors, computational modeling, RNAi, and pharmacological Ca2+ manipulation

    PMID:20051520 PMID:20071468

    Open questions at the time
    • Single lab for the accelerator model
    • Relationship between scaffold kinetics and the holophosphatase activity not reconciled
  6. 2012 High

    Showed that SHOC2 endosomal trafficking is functionally required, localizing to Rab7 late endosomes in a RAS- and clathrin-dependent manner to drive ERK activation, which the S2G mutant fails to do.

    Evidence Live-cell imaging, RNAi/dominant-negative epistasis, and rescue experiments

    PMID:22606262

    Open questions at the time
    • Identity of endosomal targeting machinery not fully defined
    • Whether holophosphatase activity occurs at endosomes unresolved
  7. 2013 High

    Identified SCRIB as a competing PP1-regulatory antagonist within the SHOC2 complex and mapped SHOC2 domains, establishing competitive regulation of RAF dephosphorylation.

    Evidence MS, Co-IP, in vitro phosphatase competition, and domain deletion analysis

    PMID:23805200 PMID:24211266

    Open questions at the time
    • Domain assignments later refined by structural work
    • Physiological contexts where SCRIB competition dominates not defined
  8. 2014 Medium

    Established ubiquitin-mediated control of the scaffold: HUWE1 ubiquitinates SHOC2 and RAF-1 as a switch for RAF activity, and a RASopathy M173I mutation impairing PP1C binding causes insufficient RAF activation.

    Evidence Co-IP, ubiquitination assays, siRNA, and rescue/ERK assays

    PMID:25022756 PMID:25137548

    Open questions at the time
    • Single-lab HUWE1 findings
    • Spatial coordination of ubiquitination with endosomal targeting unclear
  9. 2015 Medium

    Connected trafficking and turnover by showing PSMC5 drives SHOC2 endosomal translocation and displaces HUWE1 to attenuate ubiquitylation, with S2G disrupting this regulation.

    Evidence Co-IP, live imaging, and ubiquitylation assays with knockdowns

    PMID:26519477

    Open questions at the time
    • Single lab
    • Mechanism of PSMC5-mediated HUWE1 displacement not structurally defined
  10. 2018 Medium

    Identified PKC-dependent phospho-degron formation (Thr-71, Ser-297) promoting SHOC2 degradation, with FGF2 stabilizing SHOC2 by reducing this phosphorylation.

    Evidence Site-specific mutagenesis, ubiquitination and kinase assays, Co-IP

    PMID:29383184

    Open questions at the time
    • E3 ligase coupling these sites to degradation not defined here
    • Single lab
  11. 2019 High

    Resolved the downstream signaling consequence and therapeutic relevance: SHOC2-mediated S259 dephosphorylation licenses RAF heterodimerization and MEK release, governs transient ERK kinetics, and its loss sensitizes KRAS/EGFR-mutant tumors to MEK inhibition.

    Evidence SHOC2 KO/knockdown, RAF dimerization and MEK Co-IP assays, ERK time-courses, murine cancer models, and apoptosis assays

    PMID:31182717 PMID:31213532

    Open questions at the time
    • Structural basis of RAF specificity not yet resolved
    • Context-dependence across RAS isoforms incompletely mapped
  12. 2019 Medium

    Expanded SHOC2 regulation and outputs beyond MAPK: FBXW7-mediated negative feedback via Thr507 phosphorylation, mTORC1 inhibition via Raptor competition, junction-turnover control of collective migration, and VCP/p97 tuning of HUWE1 stoichiometry.

    Evidence Co-IP, ubiquitination/phospho-site mutagenesis, competition and mTORC1 assays, junction live imaging, zebrafish, and patient fibroblasts

    PMID:30808747 PMID:30865892 PMID:31091164

    Open questions at the time
    • mTORC1/Raptor and MAPK roles not integrated mechanistically
    • Several findings single-lab
    • Physiological weighting of these alternate functions unclear
  13. 2021 Medium

    Identified USP7 as a deubiquitinase switch acting in an ERK-activation-dependent manner to control HUWE1 activity within the SHOC2 module.

    Evidence Co-IP, USP7 knockdown/inhibition, and ERK/HUWE1 activity assays

    PMID:34553755

    Open questions at the time
    • Single lab
    • How USP7 timing couples to endosomal/PSMC5 events unclear
  14. 2022 High

    Provided atomic-resolution architecture of the SHOC2–MRAS–PP1C holoenzyme, showing SHOC2 cradles PP1C and MRAS via its concave LRR surface and an N-terminal RVXF motif, with GTP-MRAS-dependent assembly and RASopathy mutations enhancing affinity.

    Evidence Cryo-EM, X-ray crystallography, deep mutational scanning, and biophysical/phosphatase assays across independent studies

    PMID:35768504 PMID:35830882 PMID:35831509 PMID:36175670

    Open questions at the time
    • Structural state of RAF substrate engagement not captured
    • Endosomal/regulatory context not in the structures
  15. 2024 High

    Demonstrated a direct druggable SHOC2–RAS(Q61) interface and a novel AKT-PAK-RAF feedback route used by RASopathy variants, advancing both therapeutic targeting and disease mechanism.

    Evidence X-ray co-crystallography, CRISPR dependency screens, small-molecule screening, and pathway-inhibitor epistasis

    PMID:38881369 PMID:40335703

    Open questions at the time
    • Generality of the AKT-PAK-RAF crosstalk beyond variant cells unclear
    • In vivo efficacy/selectivity of SHOC2–RAS disruptors not established here
  16. 2025 Medium

    Linked SHOC2 to lymphatic development and cellular homeostasis via mTORC1, mitochondrial respiration, and an IRF/IFN-II senescence program, with S2G phenocopying loss.

    Evidence Zebrafish and lymphatic endothelial cell loss-of-function with mTORC1, respiration, and IFN pathway assays

    PMID:41946973

    Open questions at the time
    • Single lab
    • Connection between MAPK/holophosphatase function and the senescence phenotype not mechanistically bridged

Open questions

Synthesis pass · forward-looking unresolved questions
  • How SHOC2's distinct activities — endosomal scaffolding, the ternary holophosphatase, ubiquitin/phospho regulatory cycles, and mTORC1/migration/senescence outputs — are spatiotemporally coordinated within a single cell remains unresolved.
  • No unified model integrating trafficking, holophosphatase assembly, and turnover
  • Relative contribution of MAPK-independent functions to development unquantified
  • Structural capture of the SHOC2 complex engaging RAF substrate is lacking

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 4 GO:0008092 cytoskeletal protein binding 3 GO:0098772 molecular function regulator activity 3 GO:0140096 catalytic activity, acting on a protein 3
Localization
GO:0005886 plasma membrane 3 GO:0005634 nucleus 2 GO:0005768 endosome 2 GO:0005829 cytosol 1
Pathway
R-HSA-162582 Signal Transduction 5 R-HSA-1643685 Disease 4 R-HSA-1266738 Developmental Biology 3 R-HSA-9612973 Autophagy 1
Partners
FBXW7HUWE1MRASPPP1CBPSMC5RAF1SCRIBUSP7
Complex memberships
SHOC2-MRAS-PP1C holophosphatase

Evidence

Reading pass · 31 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1998 C. elegans SUR-8 (SHOC2 ortholog) acts downstream of or in parallel to RAS but upstream of RAF in the RAS-MAPK pathway, as established by genetic epistasis: sur-8 loss suppresses activated ras and enhances mpk-1/ksr-1 phenotypes. The human SUR-8 homolog directly binds K-Ras and N-Ras but not H-Ras in vitro. Genetic epistasis (suppressor/enhancer screens in C. elegans), direct protein binding assay (in vitro pull-down with RAS isoforms) Cell High 9674433
1998 SOC-2/SHOC2 encodes a leucine-rich repeat protein functioning downstream of the EGL-15 FGF receptor in C. elegans. Human SHOC-2 protein is cytoplasmically localized. SHOC2 is not observed to be tyrosine phosphorylated in response to FGF stimulation, and phosphorylation of YXNX motifs is not required for SOC-2 function in vivo. Genetic suppressor screen, subcellular localization by immunofluorescence, phosphorylation assay Proceedings of the National Academy of Sciences of the United States of America Medium 9618511
2000 Human Sur-8 (SHOC2) forms a ternary complex with Ras and Raf, interacting with both proteins simultaneously. Sur-8 enhances Ras- or EGF-induced Raf and ERK activation but has no effect on ERK activation by active Raf or MEK, and does not increase AKT or JNK activation, placing its action between Ras and Raf. Co-immunoprecipitation, pulldown, overexpression assays with epistasis (active Raf/MEK bypass), kinase activation assays Genes & development High 10783161
2005 Erbin inhibits ERK activation by disrupting the Sur-8–Ras–Raf complex: Erbin's LRR domain interacts with Sur-8 and reduces Sur-8 binding to active Ras and Raf. Erbin knockdown increases Sur-8–Ras/Raf interaction and ERK activation. Co-immunoprecipitation, Erbin shRNA knockdown, reporter assays, interaction mapping The Journal of biological chemistry Medium 16301319
2006 SHOC2 (Sur-8) and the catalytic subunit of protein phosphatase 1 (PP1c) form a complex that acts as a highly specific M-Ras effector. This SHOC2-PP1c holoenzyme dephosphorylates the inhibitory S259 site on RAF (bound to M-Ras or Ras), thereby activating RAF and the MAPK pathway. SHOC2 function is essential for MAPK (but not PI3K) pathway activation by growth factors in tumor cells. Proteomics (mass spectrometry), Co-immunoprecipitation, in vitro phosphatase assay, RNAi knockdown with pathway readouts Molecular cell High 16630891
2009 The disease-causing S2G mutation in SHOC2 introduces an N-myristoylation site (requires N-terminal glycine), causing aberrant constitutive targeting of SHOC2 to the plasma membrane and impaired translocation to the nucleus upon growth factor stimulation. This mislocalization results in cell-type-specific enhancement of MAPK activation. N-myristoylation assay, subcellular fractionation/live imaging, mutant expression in mammalian cells and C. elegans, MAPK activation assays Nature genetics High 19684605
2010 SHOC2 (Shoc2/SUR-8) acts as a scaffold that accelerates both the association and dissociation of Ras–Raf interaction (accelerator model), as demonstrated by FRET biosensor live-cell imaging and computational modeling. SHOC2 knockdown reduces MEK/ERK phosphorylation but not Ras activation. FRET biosensor (live-cell imaging), RNAi knockdown, computational modeling The Journal of biological chemistry High 20051520
2010 Shoc2 scaffold protein is required for Ca²⁺/calmodulin-dependent activation of Raf1 at the plasma membrane downstream of Ras. Ca²⁺-dependent Raf1 activation was abolished by Shoc2 knockdown, demonstrating Shoc2 integrates Ras and Ca²⁺ signaling inputs at Raf1. FRET biosensor, RNAi knockdown, pharmacological manipulation of Ca²⁺/calmodulin, synthetic GEF (eGRF) system Molecular biology of the cell Medium 20071468
2010 Endothelial-specific deletion of SUR-8 in mice causes late embryonic lethality with cardiac defects including hypoplastic endocardial cushions due to reduced endothelial-mesenchymal transformation, but ERK activation is not affected in mutant endothelial cells, indicating SUR-8 acts in an ERK-independent pathway during atrioventricular cushion development. Conditional (endothelial-specific) knockout mouse, histological analysis, ERK activation assays Developmental dynamics Medium 20549726
2012 Shoc2 localizes to late endosomes (Rab7-positive) upon EGFR activation in a RAS-activity- and clathrin-dependent manner. Endosomal targeting is required for ERK1/2 activation at physiological EGF concentrations. The disease-causing S2G myristoylated mutant is excluded from late endosomes (found on plasma membrane and early endosomes) and fails to rescue ERK1/2 activation in Shoc2-depleted cells. Live-cell imaging (RFP-tagged Shoc2), RNAi (clathrin, H-RAS dominant-negative), rescue experiments, subcellular fractionation PloS one High 22606262
2012 SHOC2 (Sur-8) and CRAF mediate ERK1/2 reactivation in BRAF(V600E)/NRAS(Q61K) cells during RAF inhibitor treatment. ERK1/2 activation and resistance to apoptosis in these cells require the RAF-binding site of NRAS and are modulated by SHOC-2 expression. siRNA knockdown, kinase activation assays, apoptosis assays, mutant expression The Journal of biological chemistry Medium 23076151
2013 SHOC2 forms a macromolecular complex with MRAS and SCRIB. SCRIB functions as a PP1-regulatory protein and antagonizes SHOC2-mediated RAF dephosphorylation through competition for PP1 molecules within the same complex. SHOC2 function is selectively required for malignant properties of RAS-mutant tumor cells; MRAS and SHOC2 play a key role in polarized migration. Co-immunoprecipitation, mass spectrometry, shRNA knockdown, RAF dephosphorylation assay, migration assays Molecular cell High 24211266
2013 SHOC2 has two main structural domains: an N-terminal non-LRR domain mediating binding to both M-Ras and Raf-1, and a C-terminal LRR region containing a late endosomal targeting motif. M-Ras binding to Shoc2 is independent of M-Ras GTPase activity. Domain deletion/mutation analysis, Co-immunoprecipitation, rescue experiments in Shoc2-depleted cells PloS one Medium 23805200
2014 A novel SHOC2 mutation (M173I) causes a Rasopathy by impairing SHOC2 binding to PP1c, leading to insufficient RAF-1 kinase activation and failure to fully rescue ERK1/2 activity in SHOC2-depleted cells. Co-immunoprecipitation, rescue assay in SHOC2-depleted cells, ERK1/2 phosphorylation assay Human mutation Medium 25137548
2014 HUWE1 E3 ubiquitin ligase is a binding partner and regulator of Shoc2: HUWE1 mediates ubiquitination of Shoc2 (controlling Shoc2 levels) and also controls ubiquitination and levels of RAF-1 within the Shoc2 complex. HUWE1-mediated Shoc2 ubiquitination acts as a switch regulating RAF-1 kinase activity transition from active to inactive state. Co-immunoprecipitation, ubiquitination assays, siRNA knockdown, ERK1/2 pathway activation assays Molecular and cellular biology Medium 25022756
2015 The AAA+ ATPase PSMC5 is a binding partner of Shoc2 that triggers Shoc2 translocation to endosomes. At endosomes, PSMC5 displaces HUWE1 from the Shoc2 scaffold complex, attenuating ubiquitylation of both Shoc2 and RAF-1. The Noonan-like S2G mutation alters Shoc2 subcellular distribution, reducing PSMC5 accessibility and thereby altering Shoc2 ubiquitylation. Co-immunoprecipitation, subcellular fractionation/live imaging, ubiquitylation assays, knockdown experiments Journal of cell science Medium 26519477
2015 Sur8/Shoc2 interacts with the p110α subunit of PI3K (in addition to Ras and Raf), with interactions increased in an EGF- and oncogenic Ras-dependent manner. Sur8 regulates cell migration and invasion via PI3K-dependent Rac activation and MMP upregulation. Co-immunoprecipitation, kinase inhibitor experiments, migration/invasion assays, lentiviral knockdown Oncotarget Medium 26384305
2016 SHOC2 nuclear-cytoplasmic shuttling requires LRRs 1–13 for nuclear import and constitutive plasma membrane targeting of S2G, while the KEKE motif-rich N-terminal region is necessary for efficient nuclear export. SHOC2 trapping at different subcellular compartments has distinct impacts on ERK signaling strength and dynamics, suggesting a dual modulatory role at different intracellular sites. Domain deletion/mutation constructs, live-cell imaging, subcellular fractionation, ERK activation assays Human molecular genetics Medium 27466182
2017 PKCα and PKCδ phosphorylate Sur8 at Thr-71 and Ser-297, respectively, promoting polyubiquitin-dependent degradation of Sur8. FGF2 stabilizes Sur8 by reducing this PKC-mediated phosphorylation and degradation. Phosphorylation mutagenesis, ubiquitination assays, kinase activity assays, co-immunoprecipitation Oncotarget Medium 29383184
2018 The MRAS-SHOC2-PP1 heterotrimeric holoenzyme dephosphorylates the inhibitory S259 site on RAF kinases; MRAS and SHOC2 function as PP1 regulatory subunits conferring striking substrate specificity toward RAF. Membrane localization of MRAS is required for efficient RAF dephosphorylation in cells. SHOC2's predicted structure resembles the A subunit of PP2A. Multiple SHOC2 regions and MRAS switch I/interswitch residues mediate complex formation. Noonan syndrome mutations in SHOC2, MRAS, and PPP1CB invariably promote ternary complex formation. In vitro phosphatase assay, Co-immunoprecipitation, membrane targeting experiments, mutagenesis, structural prediction Proceedings of the National Academy of Sciences of the United States of America High 30348783
2019 SHOC2 complex (SHOC2-MRAS-PP1)-mediated S259 RAF dephosphorylation is critically required for growth factor-induced RAF heterodimerization and MEK dissociation from BRAF. SHOC2 is essential for a rapid transient phase of ERK activation induced by EGF, while a slow sustained phase driven by palmitoylated H/N-RAS and CRAF is SHOC2-independent. KRAS mutant cells preferentially rely on SHOC2 for ERK signaling under anchorage-independent conditions. SHOC2 knockout/knockdown, RAF dimerization assays, MEK co-immunoprecipitation, ERK activation time-course, anchorage-independent growth assays Proceedings of the National Academy of Sciences of the United States of America High 31213532
2019 SHOC2 deletion prevents MEKi-induced RAF dimerization, leading to more potent and durable ERK pathway suppression and BIM-dependent apoptosis. Systemic SHOC2 ablation in adult mice is relatively well tolerated. SHOC2 deletion selectively sensitizes KRAS- and EGFR-mutant NSCLC cells to MEK inhibitors. Genetic SHOC2 knockout (CRISPR), murine autochthonous cancer models, RAF dimerization assays, apoptosis assays (BIM), combination drug treatment Nature communications High 31182717
2019 SHOC2 is a substrate of the FBXW7 E3 ubiquitin ligase. Growth stimuli trigger SHOC2 phosphorylation on Thr507 by the MAPK signal, which facilitates FBXW7 binding for ubiquitylation and degradation, establishing a negative feedback loop. Additionally, SHOC2 selectively binds Raptor (mTORC1 component) to competitively inhibit Raptor-mTOR binding, inactivating mTORC1 and inducing autophagy; Raptor binding to SHOC2 inhibits SHOC2-RAS binding to block MAPK signaling. Co-immunoprecipitation, ubiquitination assays, phosphorylation site mapping/mutagenesis (Thr507), mTORC1 activity assays, competitive binding assays Cell reports Medium 30865892
2019 M-Ras/Shoc2 signaling contributes to E-cadherin/p120-catenin junction turnover required for collective cell migration. Activated M-Ras recruits Shoc2 to cell surface junctions. Loss of Shoc2 reduces junction turnover and impairs collective migration. The regulatory effect requires downstream ERK cascade activation and involves phosphoregulation of p120-catenin. The myristoylated Shoc2 S2G Noonan mutant causes gain-of-function increased junction turnover and less cohesive migration. Dominant-negative M-Ras expression, SHOC2 knockdown/reconstitution, E-cadherin/p120-catenin co-immunoprecipitation, live-cell imaging of junction dynamics, zebrafish embryo gastrulation assay Proceedings of the National Academy of Sciences of the United States of America High 30808747
2019 VCP/p97 ATPase activity controls stoichiometry of HUWE1 in the Shoc2 complex and modulates HUWE1-mediated allosteric ubiquitination of Shoc2 and RAF-1. Abrogated VCP ATPase activity augments Shoc2/RAF-1 ubiquitination and alters RAF-1 phosphorylation and ERK1/2 signaling. Fibroblasts from IBMPFD patients with germline VCP mutations show imbalanced Shoc2 ubiquitination and ERK1/2 phosphorylation. Co-immunoprecipitation, ubiquitination assays, VCP ATPase mutant expression, patient-derived fibroblasts Molecular biology of the cell Medium 31091164
2021 USP7, a ubiquitin-specific protease, interacts with Shoc2 in an ERK1/2-activation-dependent manner. Within the Shoc2 module, USP7 functions as a molecular 'switch' controlling HUWE1 E3 ligase activity and the HUWE1-induced regulatory feedback loop. Disruption of Shoc2-USP7 binding leads to aberrant ERK1/2 axis activation. Co-immunoprecipitation, USP7 knockdown/inhibition, ERK1/2 activation assays, HUWE1 activity assays Journal of cell science Medium 34553755
2022 Cryo-EM structures of the SHOC2-MRAS-PP1C complex (two independent studies, ~3 Å resolution) reveal a tripartite architecture: crescent-shaped SHOC2 acts as a cradle bridging PP1C and MRAS through its concave LRR surface. SHOC2 also engages PP1C through an N-terminal disordered region containing a cryptic RVXF motif. Complex assembly is initiated by SHOC2-PP1C interaction and stabilized by GTP-loaded MRAS. RASopathy mutations reside at protein-protein interfaces and enhance holoenzyme affinity. Deep mutational scanning comprehensively maps functional residues of SHOC2. Multiple RAS isoforms can substitute for MRAS in a GTP-dependent manner. Cryo-electron microscopy, X-ray crystallography, deep mutational scanning, biophysical binding assays, mutagenesis Nature High 35768504 35830882 35831509 36175670
2022 Crystal structure of the SHOC2-MRAS-PP1C complex shows all three proteins synergistically interact with each other. PP1C substrate specificity toward RAF is enhanced upon interaction with both SHOC2 and MRAS. Complex forms only when MRAS is GTP-bound. SHOC2 functions as scaffolding protein bringing PP1C and MRAS together. Noonan syndrome mutations enhance complex formation. X-ray crystallography, in vitro phosphatase assay with RAF substrates, biophysical binding assays, mutagenesis Nature structural & molecular biology High 36175670
2024 NRAS(Q61R) forms a direct protein-protein interaction with SHOC2, revealed by X-ray co-crystal structure. SHOC2 is a dependency of RAS(Q61*) tumors in a nucleotide-state-dependent manner. Small molecules disrupting the SHOC2–RAS(Q61*) interaction inhibit MAPK signaling and proliferation in RAS-mutant cancer models. X-ray co-crystallography, CRISPR dependency screens, in vitro high-throughput small-molecule screening, MAPK signaling assays, proliferation assays Nature High 40335703
2024 In cells expressing NSLH-associated Shoc2 variants, when both AKT and ERK1/2 pathways are activated downstream of EGFR, AKT signaling triggers PAK activation followed by Raf-1/MEK1/2 phosphorylation and ERK1/2 activation, revealing a previously unrecognized AKT-PAK-RAF feedback crosstalk. In contrast, when ERK1/2 is the primary EGFR effector, Shoc2 variants cannot upregulate ERK1/2 to wild-type levels. Mutant expression/reconstitution, pathway inhibitor epistasis, ERK1/2 and AKT phosphorylation assays Human molecular genetics Medium 38881369
2025 Loss of Shoc2 in zebrafish and lymphatic endothelial cells results in near-complete loss of lymphatic vasculature and cellular senescence. Mechanistically, Shoc2 loss increases mTORC1 signaling, impairs mitochondrial respiration, and triggers an IRF/IFN-II innate immune response leading to senescence. The NSLH-causing S2G variant phenocopies Shoc2 loss in this context. Zebrafish genetic loss-of-function, in vitro lymphatic endothelial cell assays, mTORC1 activity assays, mitochondrial respiration assay, IFN pathway assays Cell death and differentiation Medium 41946973

Source papers

Stage 0 corpus · 78 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2009 Mutation of SHOC2 promotes aberrant protein N-myristoylation and causes Noonan-like syndrome with loose anagen hair. Nature genetics 313 19684605
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
1998 SUR-8, a conserved Ras-binding protein with leucine-rich repeats, positively regulates Ras-mediated signaling in C. elegans. Cell 175 9674433
2000 The leucine-rich repeat protein SUR-8 enhances MAP kinase activation and forms a complex with Ras and Raf. Genes & development 116 10783161
1998 soc-2 encodes a leucine-rich repeat protein implicated in fibroblast growth factor receptor signaling. Proceedings of the National Academy of Sciences of the United States of America 99 9618511
2013 An MRAS, SHOC2, and SCRIB complex coordinates ERK pathway activation with polarity and tumorigenic growth. Molecular cell 96 24211266
2005 Erbin inhibits RAF activation by disrupting the sur-8-Ras-Raf complex. The Journal of biological chemistry 88 16301319
2019 Synthetic Lethal Interaction of SHOC2 Depletion with MEK Inhibition in RAS-Driven Cancers. Cell reports 78 31577942
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
2022 Structure-function analysis of the SHOC2-MRAS-PP1C holophosphatase complex. Nature 65 35831509
2019 SHOC2 phosphatase-dependent RAF dimerization mediates resistance to MEK inhibition in RAS-mutant cancers. Nature communications 65 31182717
2013 Expanding the SHOC2 mutation associated phenotype of Noonan syndrome with loose anagen hair: structural brain anomalies and myelofibrosis. American journal of medical genetics. Part A 54 23918763
2010 The scaffold protein Shoc2/SUR-8 accelerates the interaction of Ras and Raf. The Journal of biological chemistry 51 20051520
2012 SHOC2 and CRAF mediate ERK1/2 reactivation in mutant NRAS-mediated resistance to RAF inhibitor. The Journal of biological chemistry 47 23076151
2022 Structural basis for SHOC2 modulation of RAS signalling. Nature 43 35768504
2019 The FBXW7-SHOC2-Raptor Axis Controls the Cross-Talks between the RAS-ERK and mTORC1 Signaling Pathways. Cell reports 43 30865892
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
2010 Mutation analysis of the SHOC2 gene in Noonan-like syndrome and in hematologic malignancies. Journal of human genetics 40 20882035
2019 SHOC2 complex-driven RAF dimerization selectively contributes to ERK pathway dynamics. Proceedings of the National Academy of Sciences of the United States of America 39 31213532
2014 HUWE1 is a molecular link controlling RAF-1 activity supported by the Shoc2 scaffold. Molecular and cellular biology 35 25022756
2015 Sur8/Shoc2 promotes cell motility and metastasis through activation of Ras-PI3K signaling. Oncotarget 32 26384305
2010 Ras and calcium signaling pathways converge at Raf1 via the Shoc2 scaffold protein. Molecular biology of the cell 32 20071468
2014 A Novel SHOC2 Variant in Rasopathy. Human mutation 31 25137548
2010 Endothelial SUR-8 acts in an ERK-independent pathway during atrioventricular cushion development. Developmental dynamics : an official publication of the American Association of Anatomists 31 20549726
2019 The MTORC1-mediated autophagy is regulated by the FBXW7-SHOC2-RPTOR axis. Autophagy 30 31010381
2015 Spatial control of Shoc2-scaffold-mediated ERK1/2 signaling requires remodeling activity of the ATPase PSMC5. Journal of cell science 29 26519477
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
2014 Severe craniosynostosis with Noonan syndrome phenotype associated with SHOC2 mutation: clinical evidence of crosslink between FGFR and RAS signaling pathways. American journal of medical genetics. Part A 28 25123707
2016 The function of Shoc2: A scaffold and beyond. Communicative & integrative biology 26 27574535
2014 Phenotypic variability associated with the invariant SHOC2 c.4A>G (p.Ser2Gly) missense mutation. American journal of medical genetics. Part A 25 25331583
2012 Noonan syndrome due to a SHOC2 mutation presenting with fetal distress and fatal hypertrophic cardiomyopathy in a premature infant. American journal of medical genetics. Part A 25 22528146
2011 Co-occurring SHOC2 and PTPN11 mutations in a patient with severe/complex Noonan syndrome-like phenotype. American journal of medical genetics. Part A 24 21548061
2022 lncRNA MALAT1 regulates the resistance of breast cancer cells to paclitaxel via the miR-497-5p/SHOC2 axis. Pharmacogenomics 23 36420706
2021 A Leucine-Rich Repeat Protein Provides a SHOC2 the RAS Circuit: a Structure-Function Perspective. Molecular and cellular biology 23 33526449
2019 Clinical and functional characterization of a novel RASopathy-causing SHOC2 mutation associated with prenatal-onset hypertrophic cardiomyopathy. Human mutation 23 31059601
2012 Shoc2 is targeted to late endosomes and required for Erk1/2 activation in EGF-stimulated cells. PloS one 23 22606262
2014 Hydrops fetalis in a preterm newborn heterozygous for the c.4A>G SHOC2 mutation. American journal of medical genetics. Part A 22 24458587
2013 Functional Integration of the Conserved Domains of Shoc2 Scaffold. PloS one 22 23805200
2012 Clinical Heterogeneity in two patients with Noonan-like Syndrome associated with the same SHOC2 mutation. Italian journal of pediatrics 21 22995099
2019 MiR-299-3p functions as a tumor suppressor in thyroid cancer by regulating SHOC2. European review for medical and pharmacological sciences 20 30657565
2011 Sur8/Shoc2 involves both inhibition of differentiation and maintenance of self-renewal of neural progenitor cells via modulation of extracellular signal-regulated kinase signaling. Stem cells (Dayton, Ohio) 20 21732489
2020 SHOC2 Is a Critical Modulator of Sensitivity to EGFR-TKIs in Non-Small Cell Lung Cancer Cells. Molecular cancer research : MCR 19 33106373
2024 Small-molecule targeting BCAT1-mediated BCAA metabolism inhibits the activation of SHOC2-RAS-ERK to induce apoptosis of Triple-negative breast cancer cells. Journal of advanced research 18 39490614
2016 SHOC2 subcellular shuttling requires the KEKE motif-rich region and N-terminal leucine-rich repeat domain and impacts on ERK signalling. Human molecular genetics 18 27466182
2014 Rare copy number variations containing genes involved in RASopathies: deletion of SHOC2 and duplication of PTPN11. Molecular cytogenetics 17 24739123
2025 Targeting the SHOC2-RAS interaction in RAS-mutant cancers. Nature 15 40335703
2019 Hematopoietic and neural crest defects in zebrafish shoc2 mutants: a novel vertebrate model for Noonan-like syndrome. Human molecular genetics 15 30329053
2016 Shoc2-tranduced ERK1/2 motility signals--Novel insights from functional genomics. Cellular signalling 15 26876614
2018 Systematic identification of Celastrol-binding proteins reveals that Shoc2 is inhibited by Celastrol. Bioscience reports 14 30333251
2022 Shoc2 recognizes bacterial flagellin and mediates antibacterial Erk/Stat signaling in an invertebrate. PLoS pathogens 13 35073369
2022 Expanding the molecular spectrum of pathogenic SHOC2 variants underlying Mazzanti syndrome. Human molecular genetics 13 35348676
2022 The Sag-Shoc2 axis regulates conversion of mPanINs to cystic lesions in Kras pancreatic tumor model. Cell reports 12 36543126
2023 LncRNA FALEC increases the proliferation, migration and drug resistance of cholangiocarcinoma through competitive regulation of miR-20a-5p/SHOC2 axis. Aging 11 37166421
2019 VCP/p97 controls signals of the ERK1/2 pathway transmitted via the Shoc2 scaffolding complex: novel insights into IBMPFD pathology. Molecular biology of the cell 11 31091164
2023 RAS and SHOC2 Roles in RAF Activation and Therapeutic Considerations. Annual review of cancer biology 10 38882927
2021 The role of USP7 in the Shoc2-ERK1/2 signaling axis and Noonan-like syndrome with loose anagen hair. Journal of cell science 8 34553755
2016 Sur8 mediates tumorigenesis and metastasis in colorectal cancer. Experimental & molecular medicine 7 27469030
2023 Structural insights into the role of SHOC2-MRAS-PP1C complex in RAF activation. The FEBS journal 6 37074066
2023 SHOC2 mediates the drug-resistance of triple-negative breast cancer cells to everolimus. Cancer biology & therapy 6 37170083
2022 Shoc2 controls ERK1/2-driven neural crest development by balancing components of the extracellular matrix. Developmental biology 6 36265687
2019 SUR-8 interacts with PP1-87B to stabilize PERIOD and regulate circadian rhythms in Drosophila. PLoS genetics 6 31710605
2017 Stabilization of Sur8 via PKCα/δ degradation promotes transformation and migration of colorectal cancer cells. Oncotarget 5 29383184
2024 SHOC2 plays an oncogenic or tumor-suppressive role by differentially targeting the MAPK and mTORC1 signals in liver cancer. Life medicine 4 39871893
2022 Case report: A de novo RASopathy-causing SHOC2 variant in a Chinese girl with noonan syndrome-like with loose anagen hair. Frontiers in genetics 4 36579329
2019 Single-domain antibodies for functional targeting of the signaling scaffold Shoc2. Molecular immunology 4 31869742
2016 Data set for transcriptional response to depletion of the Shoc2 scaffolding protein. Data in brief 4 27077079
2020 SHOC2 scaffold protein modulates daunorubicin-induced cell death through p53 modulation in lymphoid leukemia cells. Scientific reports 3 32938995
2019 Recurrent Erythema Nodosum in a Child with a SHOC2 Gene Mutation. Yonago acta medica 3 30962759
2014 Shoc2/Sur8 protein regulates neurite outgrowth. PloS one 3 25514808
2023 Co-Occurring Thrombotic Thrombocytopenic Purpura and Autoimmune Hemolytic Anemia in a Child Carrying the Pathogenic SHOC2 c.4A>G (p.Ser2Gly) Variant. The American journal of case reports 2 38019730
2024 circCPA4 induces malignant behaviors of prostate cancer via miR-491-5p/SHOC2 feedback loop. Clinics (Sao Paulo, Brazil) 1 38219533
2026 Signaling scaffold Shoc2 regulates lymphangiogenesis by suppressing mTORC1-mediated IFN responses. Cell death and differentiation 0 41946973
2026 Expression of LIFR in tumor and SHOC2, YAP1 in plasma mRNA as potential biomarkers in KRAS G12C NSCLC. Scientific reports 0 42185401
2025 Signaling scaffold Shoc2 regulates lymphangiogenesis by suppressing mTORC1-mediated IFN responses. bioRxiv : the preprint server for biology 0 40196569
2024 The expression of congenital Shoc2 variants induces AKT-dependent crosstalk activation of the ERK1/2 pathway. Human molecular genetics 0 38881369
2023 The expression of congenital Shoc2 variants induces AKT-dependent feedback activation of the ERK1/2 pathway. bioRxiv : the preprint server for biology 0 38187642
2022 The Clinical and Molecular Assessment of Iranian Families with Severe Congenital Neutropenia, Identification of HYOU1 and SHOC2 as Potential Novel Gene Defects. Iranian journal of allergy, asthma, and immunology 0 35822684

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