ArticleNeoplasia (New York, N.Y.)2014
KRAS protein stability is regulated through SMURF2: UBCH5 complex-mediated β-TrCP1 degradation.
Article in Neoplasia (New York, N.Y.), 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 69 papers.
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Who cites it
69 citing papers in PubMed, 96 citations in OpenAlex.
- Adagrasib with or without Cetuximab in Colorectal Cancer with MutatedThe New England journal of medicine · 2023Trial
- Article
- Rewiring KRAS-driven cancers through the ubiquitin-proteasome system: therapeutic opportunities with a focus on deubiquitinase.Experimental & molecular medicine · 2026Review
- ISGylation of γH2AX retains MDC1 and facilitates homologous recombination repair causing radioresistance in esophageal adenocarcinoma.The Journal of biological chemistry · 2026Article
- SMURF2 in Anticancer Therapy: Dual Role in Carcinogenesis and Theranostics.International journal of molecular sciences · 2026Review
- Novel function of GTPBP2 in promoting hepatocellular carcinoma progression through inhibition of BTRC-mediated KRAS degradation.Cancer cell international · 2026Article
- Targeted Protein Degradation in Lung Cancer: The Emerging Role of PROTAC Technology and E3 Ligases.Current medicinal chemistry · 2026Review
- Tip60-HDAC8-SMURF2-mediated β-TrCP1 degradation is a key mechanism for hypoxia-induced cell death and tissue injury.Cellular and molecular life sciences : CMLS · 2025Article
- Review
- SMURF2 Facilitates GAP17 Isoform 1 Membrane Displacement to Promote Mutant p53-KRAS Oncogenic Synergy.Molecular cancer research : MCR · 2025Article
- Ubiquitin-conjugating enzyme UBE2N modulates proteostasis in immunoproteasome-positive acute myeloid leukemia.The Journal of clinical investigation · 2025Article
- Simultaneous targeted delivery of doxorubicin and KRAS suppression by a hybrid molecule containing miR-143 and AS1411 aptamer.Scientific reports · 2025Article
- Anti-proteolytic regulation of KRAS by USP9X/NDRG3 in KRAS-driven cancer development.Nature communications · 2025Article
- Preclinical Evaluation of [ACS pharmacology & translational science · 2024Article
- Aberrant activation of a miR-101-UBE2D1 axis contributes to the advanced progression and chemotherapy sensitivity in human hepatocellular carcinoma.Cell death discovery · 2024Article
- SelK promotes glioblastoma cell proliferation by inhibiting β-TrCP1 mediated ubiquitin-dependent degradation of CDK4.Journal of experimental & clinical cancer research : CR · 2024Article
- Defining the KRAS- and ERK-dependent transcriptome in KRAS-mutant cancers.Science (New York, N.Y.) · 2024Article
- Isoform alterations in the ubiquitination machinery impacting gastrointestinal malignancies.Cell death & disease · 2024Review
- Mechanisms of RNF168 nucleosome recognition and ubiquitylation.Molecular cell · 2024Article
- Inhibition of ADAM9 promotes the selective degradation of KRAS and sensitizes pancreatic cancers to chemotherapy.Nature cancer · 2024Article
9 more citing papers are in PubMed but not listed here.
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Authors and funding
18 authors at 2 institutions in 1 country.
Funding
Abstract
Attempts to target mutant KRAS have been unsuccessful. Here, we report the identification of Smad ubiquitination regulatory factor 2 (SMURF2) and UBCH5 as a critical E3:E2 complex maintaining KRAS protein stability. Loss of SMURF2 either by small interfering RNA/short hairpin RNA (siRNA/shRNA) or by overexpression of a catalytically inactive mutant causes KRAS degradation, whereas overexpression of wild-type SMURF2 enhances KRAS stability. Importantly, mutant KRAS is more susceptible to SMURF2 loss where protein half-life decreases from >12 hours in control siRNA-treated cells to <3 hours on Smurf2 silencing, whereas only marginal differences were noted for wild-type protein. This loss of mutant KRAS could be rescued by overexpressing a siRNA-resistant wild-type SMURF2. Our data further show that SMURF2 monoubiquitinates UBCH5 at lysine 144 to form an active complex required for efficient degradation of a RAS-family E3, β-transducing repeat containing protein 1 (β-TrCP1). Conversely, β-TrCP1 is accumulated on SMURF2 loss, leading to increased KRAS degradation. Therefore, as expected, β-TrCP1 knockdown following Smurf2 siRNA treatment rescues mutant KRAS loss. Further, we identify two conserved proline (P) residues in UBCH5 critical for SMURF2 interaction; mutation of either of these P to alanine also destabilizes KRAS. As a proof of principle, we demonstrate that Smurf2 silencing reduces the clonogenic survival in vitro and prolongs tumor latency in vivo in cancer cells including mutant KRAS-driven tumors. Taken together, we show that SMURF2:UBCH5 complex is critical in maintaining KRAS protein stability and propose that targeting such complex may be a unique strategy to degrade mutant KRAS to kill cancer cells.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.