Affinage

RAB40C

Ras-related protein Rab-40C · UniProt Q96S21

Length
281 aa
Mass
31.3 kDa
Annotated
2026-06-10
13 papers in source corpus 10 papers cited in narrative 10 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

RAB40C is an atypical small GTPase that couples Rab-family membrane-targeting features to a SOCS box, allowing it to nucleate a Cullin5-based CRL ubiquitin E3 ligase that selects substrates for degradation and thereby controls lipid storage, cell adhesion, and cancer cell behavior (PMID:35512830, PMID:23638186). The protein binds GTP preferentially over GDP and carries a C-terminal extension permitting isoprenylation and palmitoylation, consistent with its membrane localization to the perinuclear recycling compartment and, prominently, to the surface of lipid droplets where recruitment increases during droplet formation and adipocyte differentiation (PMID:15160388, PMID:23638186, PMID:25702114). At lipid droplets, RAB40C drives clustering in a manner dependent on an intact SOCS box but independent of GTPase activity, and its loss causes over-accumulation of lipid droplets; DAB2IP acts as a GTPase-activating protein for RAB40C and negatively regulates this lipid droplet homeostasis function (PMID:23638186, PMID:29156729). As the substrate-recognition module of a CRL5 complex, RAB40C ubiquitylates and degrades multiple targets: it binds the ANKR2 domain of Varp to promote its proteasomal degradation and limit Tyrp1 trafficking in melanocytes (PMID:25661869), targets the PP6 subunit ANKRD28 for lysosomal degradation to derepress FAK and MOB1 phosphorylation and remodel focal adhesions in migrating cells (PMID:35512830), and controls levels of the scaffold RACK1 (PMID:30112187) and of SNX9, the latter linking RAB40C to Hippo pathway output (PMID:42245125). RAB40C expression is repressed post-transcriptionally by the microRNA let-7a and activated transcriptionally by STAT3, and in this STAT3-driven context it recruits the E3 ligase TRIM21 to promote K63-linked ubiquitination of EGFR at Lys713, stabilizing EGFR and sustaining its signaling (PMID:21349817, PMID:41350889). Through these activities RAB40C modulates cancer cell proliferation, migration, and invasion across gastric, breast, prostate, and hepatocellular models (PMID:21349817, PMID:35512830, PMID:42245125, PMID:41350889).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 2004 Medium

    Establishing RAB40C as a bona fide GTP-binding protein with membrane-targeting motifs answered whether this atypical Rab is a functional small GTPase and where it acts.

    Evidence GTP-binding assay, subcellular fractionation/immunolocalization, and domain architecture analysis after cloning from oligodendrocyte cDNA

    PMID:15160388

    Open questions at the time
    • No functional mutagenesis to test nucleotide-state-dependent activity
    • Role of the SOCS box not yet appreciated
    • Perinuclear recycling localization not linked to a specific pathway
  2. 2011 Medium

    Identifying RAB40C as a direct let-7a target placed it in a defined regulatory circuit and connected its expression to tumor cell proliferation.

    Evidence 3'-UTR luciferase reporter, let-7a overexpression with RAB40C rescue, and xenograft assay in gastric cancer cells

    PMID:21349817

    Open questions at the time
    • Molecular effector mechanism by which RAB40C drives proliferation not defined here
    • Single cancer context
    • No link yet to its later-defined E3 ligase activity
  3. 2013 High

    Defining RAB40C as a lipid droplet-associated protein whose clustering requires the SOCS box but not GTPase activity reframed it from a conventional Rab to a SOCS-box-dependent scaffold at lipid droplets.

    Evidence GFP live imaging with lipid dyes, sucrose-density fractionation, siRNA knockdown morphometrics, Co-IP with TIP47, and SOCS-box/GTPase-dead mutants

    PMID:23638186

    Open questions at the time
    • Identity of the SOCS-box-recruited ligase machinery not yet established
    • Functional consequence of the TIP47 interaction unresolved
    • Mechanism linking clustering to droplet biology unclear
  4. 2015 High

    Demonstrating SOCS-box-dependent proteasomal degradation of Varp and downstream Tyrp1 trafficking gave RAB40C its first defined substrate and tied its SOCS box to ubiquitin-mediated degradation.

    Evidence Co-IP mapping to the Varp ANKR2 domain, SOCS-box mutagenesis, proteasome inhibitor rescue, and Tyrp1 immunofluorescence in melanocytes

    PMID:25661869

    Open questions at the time
    • Identity of the full E3 ligase complex (Cullin partner) not yet shown
    • Generality beyond melanocyte trafficking unknown
  5. 2017 High

    Identifying DAB2IP as a GAP for RAB40C and showing CRISPR knockout causes lipid droplet over-accumulation established upstream regulation and a clear loss-of-function phenotype.

    Evidence Co-IP, GAP-defective DAB2IP mutant, siRNA depletion, and CRISPR knockout with lipid droplet quantification

    PMID:29156729

    Open questions at the time
    • How GTPase state intersects with SOCS-box-dependent function not reconciled
    • Substrate degraded to control droplets not identified here
  6. 2018 Medium

    Showing RAB40C ubiquitylates and degrades RACK1 generalized its E3 ligase role beyond Varp and connected it to cancer growth and immune cell migration.

    Evidence siRNA screen, ubiquitination and RACK1 stability assays, and functional readouts of cell growth and T-cell migration

    PMID:30112187

    Open questions at the time
    • Limited mechanistic detail on the ligase complex composition
    • Ubiquitin linkage type and degradation route not detailed
    • Single lab
  7. 2022 High

    Defining the Rab40c/CRL5 complex that degrades ANKRD28 to suppress PP6 and elevate FAK/MOB1 phosphorylation provided the first complete enzyme-substrate-pathway axis for RAB40C in focal adhesion and migration control.

    Evidence CRISPR knockout, Co-IP with the PP6 complex/ANKRD28, MS-identified ubiquitylation, phosphoproteomics, and focal adhesion imaging in MDA-MB-231 cells

    PMID:35512830

    Open questions at the time
    • Whether the same CRL5 assembly handles all RAB40C substrates not established
    • Spatial coordination with lipid droplet pool unresolved
  8. 2025 Medium

    Placing RAB40C downstream of STAT3 and showing it recruits TRIM21 to K63-ubiquitylate and stabilize EGFR revealed a non-degradative, signal-sustaining mode distinct from its degradative substrates.

    Evidence Co-IP, MS-identified Lys713 ubiquitination site, K63-linkage ubiquitination assay, STAT3 ChIP/reporter, and growth/xenograft assays in hepatocellular carcinoma

    PMID:41350889

    Open questions at the time
    • How RAB40C reconciles substrate-degrading and substrate-stabilizing activities mechanistically unclear
    • Whether CRL5 is involved in EGFR stabilization not addressed
    • Single lab
  9. 2026 Medium

    Identifying SNX9 as a RAB40C degradation substrate linked to Hippo signaling extended the substrate repertoire and connected RAB40C to another oncogenic pathway in prostate cancer.

    Evidence Co-IP, siRNA knockdown with SNX9 immunoblot, proteasome inhibitor rescue, double-knockdown epistasis, and Hippo target immunoblot

    PMID:42245125

    Open questions at the time
    • Direct ubiquitination of SNX9 by RAB40C not demonstrated biochemically
    • Mechanistic link to Hippo effectors indirect
    • Limited methodological detail

Open questions

Synthesis pass · forward-looking unresolved questions
  • How RAB40C selects among its diverse substrates, and whether its membrane targeting (lipid droplet vs recycling compartment) spatially partitions degradative versus stabilizing E3 ligase activities, remains unresolved.
  • No structural model of the RAB40C CRL5 complex with substrates
  • Determinants of K48- vs K63-linkage and proteasomal vs lysosomal routing unknown
  • Physiological (non-cancer) roles largely uncharacterized in the corpus

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016874 ligase activity 3 GO:0140096 catalytic activity, acting on a protein 3 GO:0003924 GTPase activity 2 GO:0060090 molecular adaptor activity 2
Localization
GO:0005811 lipid droplet 2 GO:0005783 endoplasmic reticulum 1
Pathway
R-HSA-162582 Signal Transduction 3 R-HSA-1643685 Disease 3 R-HSA-392499 Metabolism of proteins 3
Complex memberships
CRL5 (Cullin5 ubiquitin E3 ligase)

Evidence

Reading pass · 10 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2004 Rab40c was cloned from an oligodendrocyte cDNA library and found to bind GTPγS (Kd ~21 µM) with higher affinity for GTP than GDP, and is localized in the perinuclear recycling compartment, suggesting involvement in endocytic receptor recycling; the carboxyl-terminal extension contains motifs permitting isoprenylation and palmitoylation. GTP-binding assay (radiolabeled nucleotide binding), subcellular fractionation/immunolocalization, sequence/structural analysis of domain architecture Journal of neuroscience research Medium 15160388
2011 RAB40C is a direct transcriptional target of the microRNA let-7a; let-7a binds the 3'-UTR of RAB40C mRNA to repress its expression post-transcriptionally, and RAB40C mediates the pro-proliferative effects of let-7a loss in gastric cancer cells. 3'-UTR luciferase reporter assay, let-7a overexpression with RAB40C rescue, in vivo xenograft model Carcinogenesis Medium 21349817
2013 Rab40c localizes to lipid droplet surfaces (not Golgi or endosomal compartments) and to ERGIC-53-positive structures, is increasingly recruited during lipid droplet formation and maturation, and its knockdown reduces lipid droplet size. Overexpression causes lipid droplet clustering dependent on an intact SOCS box but independent of GTPase activity. Rab40c physically interacts with TIP47 and displays self-interaction; the SOCS box is required for clustering. GFP-fusion live imaging and co-localization with neutral lipid dyes (Oil Red O, Nile Red), sucrose-density-gradient fractionation, siRNA knockdown with morphometric analysis, Co-IP (Rab40c–TIP47), SOCS-box deletion mutants, GTPase-dead mutants PloS one High 23638186
2015 Rab40C binds the ANKR2 domain of Varp via a direct protein–protein interaction and promotes proteasomal degradation of Varp in a SOCS-box-dependent manner; this reduces Tyrp1 trafficking in melanocytes. Conversely, Rab40C knockdown increases Varp levels and also reduces Tyrp1 signals. Co-IP (Rab40C–Varp ANKR2 domain), overexpression and knockdown in melanocytes, proteasome inhibitor rescue, immunofluorescence of Tyrp1 trafficking Biology open High 25661869
2015 Methods for analyzing Rab40c association with lipid droplets were established, confirming localization via fluorescence confocal microscopy and sucrose-density centrifugation fractionation, and demonstrating that Rab40c protein level increases during adipocyte differentiation of 3T3-L1 cells. Fluorescence confocal microscopy (GFP-Rab40c + lipid-dye co-localization), sucrose-density centrifugation fractionation, immunoblot during adipocyte differentiation Methods in molecular biology Medium 25702114
2017 DAB2IP, a RasGAP, binds RAB40C primarily through its GAP domain and acts as a GTPase-activating protein (GAP) for RAB40C. DAB2IP overexpression negatively regulates RAB40C's effect on lipid droplet homeostasis; a GAP-defective DAB2IP mutant and siRNA depletion of DAB2IP both confirm this regulatory relationship. RAB40C deletion by CRISPR-Cas9 causes over-accumulation of lipid droplets. Co-IP (RAB40C–DAB2IP), GAP-defective DAB2IP mutant overexpression, siRNA depletion of DAB2IP, CRISPR-Cas9 knockout of RAB40C with lipid droplet quantification Oncotarget High 29156729
2018 RAB40C functions as a ubiquitin E3 ligase (via its SOCS box recruiting a CRL complex) responsible for ubiquitination and proteasomal degradation of the scaffolding protein RACK1; RAB40C-mediated control of RACK1 levels affects cancer cell growth and T-cell migration. siRNA screen identifying RAB40C, ubiquitination assay, RACK1 stability assay following RAB40C knockdown, functional readouts (cell growth, T-cell migration) Future science OA Medium 30112187
2022 Rab40c forms a Cullin5-based ubiquitin E3 ligase complex (Rab40c/CRL5), binds the PP6 phosphatase complex subunit ANKRD28, and promotes its ubiquitylation leading to lysosomal degradation. This reduces PP6 activity, increases phosphorylation of FAK and MOB1, and regulates focal adhesion number, size, and distribution in migrating MDA-MB-231 cells. Rab40c knockout cells (CRISPR), Co-IP (Rab40c–PP6 complex/ANKRD28), mass spectrometry identification of ubiquitylation, phosphoproteomics (FAK, MOB1 phosphorylation), immunofluorescence of focal adhesions Life science alliance High 35512830
2025 RAB40C is a downstream transcriptional target of STAT3 and promotes K63-linked ubiquitination of EGFR at Lys713 by recruiting the E3 ligase TRIM21, thereby stabilizing EGFR protein and sustaining downstream EGFR signaling in hepatocellular carcinoma cells. Co-immunoprecipitation (RAB40C–TRIM21–EGFR), mass spectrometry identification of ubiquitination site (Lys713), ubiquitination assay (K63-linked), STAT3 ChIP/reporter linking STAT3 to RAB40C transcription, cell growth/migration and xenograft assays Cell communication and signaling Medium 41350889
2026 RAB40C interacts with SNX9 and promotes its degradation via the ubiquitin-proteasome pathway; silencing RAB40C increases SNX9 levels. This RAB40C–SNX9 axis influences Hippo signaling pathway target proteins and modulates proliferation, migration, and invasion of prostate adenocarcinoma cells. Co-IP (RAB40C–SNX9), siRNA knockdown of RAB40C with SNX9 immunoblot, proteasome inhibitor rescue, double-knockdown epistasis, Hippo pathway target immunoblot Central-European journal of immunology Medium 42245125

Source papers

Stage 0 corpus · 13 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2011 Low-level expression of let-7a in gastric cancer and its involvement in tumorigenesis by targeting RAB40C. Carcinogenesis 90 21349817
2013 Small GTPase Rab40c associates with lipid droplets and modulates the biogenesis of lipid droplets. PloS one 35 23638186
2004 Vesicle transport in oligodendrocytes: probable role of Rab40c protein. Journal of neuroscience research 33 15160388
2015 Rab40C is a novel Varp-binding protein that promotes proteasomal degradation of Varp in melanocytes. Biology open 24 25661869
2018 RAB40C regulates RACK1 stability via the ubiquitin-proteasome system. Future science OA 17 30112187
2022 Rab40c regulates focal adhesions and PP6 activity by controlling ANKRD28 ubiquitylation. Life science alliance 13 35512830
2022 Small GTPase Rab40C is upregulated by 20-hydroxyecdysone and insulin pathways to regulate ovarian development and fecundity. Insect science 11 35349758
2017 A RasGAP, DAB2IP, regulates lipid droplet homeostasis by serving as GAP toward RAB40C. Oncotarget 11 29156729
2021 RAB40C Gene Polymorphisms Were Associated with Alcohol-Induced Osteonecrosis of the Femoral Head. International journal of general medicine 5 34305407
2015 Analysis of biogenesis of lipid droplets by examining Rab40c associating with lipid droplets. Methods in molecular biology (Clifton, N.J.) 5 25702114
2021 RAB40C gene polymorphisms rs62030917 and rs2269556 are associated with an increased risk of lumbar disc herniation development in the Chinese Han population. The journal of gene medicine 4 32656896
2026 RAB40C regulates SNX9 stability via the ubiquitin-proteasome system and modulates the Hippo signaling pathway of prostate adenocarcinoma. Central-European journal of immunology 0 42245125
2025 RAB40C recruiting TRIM21 facilitates the progression of hepatocellular carcinoma by stabilizing EGFR. Cell communication and signaling : CCS 0 41350889

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