ArticleProceedings of the National Academy of Sciences of the United States of America2022
UBR2 targets myosin heavy chain IIb and IIx for degradation: Molecular mechanism essential for cancer-induced muscle wasting.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 26 papers.
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Who cites it
26 citing papers in PubMed, 30 citations in OpenAlex.
- Reorientation of the SUMOylation landscape and altered L3mbtl2-mediated transcriptional activity in cancer-associated muscle contractile dysfunction.Cell death discovery · 2026Article
- The Secretome of a Cachexia-Inducing Lung Tumor Impairs Mitochondrial Function and Skeletal Muscle Differentiation.Cancers · 2026Article
- Cancer cachexia: A tumor-driven disorder of whole-body homeostasis.Cancer cell · 2026Review
- The Conjugated Bile Acids Profile Suggests a Novel Liver-Muscle Axis Associated With Sarcopenia in Chronic Liver Disease.Liver international : official journal of the International Association for the Study of the Liver · 2026Article
- Mechanisms of protein degradation in atrophying muscles: What have we learned during the past decade?The Journal of biological chemistry · 2026Review
- Response of UBR-box E3 ubiquitin ligases and protein quality control pathways to perturbations in protein synthesis and skeletal muscle size.American journal of physiology. Cell physiology · 2025Article
- Cisplatin-Induced Skeletal Muscle Atrophy: Biomolecular Mechanisms and the Protective Role of Exercise-Induced Myokines.Biomolecules · 2025Review
- Signaling networks governing skeletal muscle growth, atrophy, and cachexiaSkeletal muscle · 2025Review
- Response of UBR-box E3 ubiquitin ligases and protein quality control pathways to perturbations in protein synthesis and skeletal muscle size.bioRxiv : the preprint server for biology · 2025Article
- Population-scale gene-based analysis of whole-genome sequencing provides insights into metabolic health.Nature genetics · 2025Article
- UBR5: A New Player in Protein Quality Control for Skeletal Muscle Growth and Remodeling.Exercise and sport sciences reviews · 2025Review
- Wearable Bioelectronics for Home-Based Monitoring and Treatment of Muscle Atrophy.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Review
- Identification of diabetes-related signatures as prognostic and therapeutic biomarkers in colon cancer.Discover oncology · 2025Article
- An alternative pocket for binding the N-degrons by the UBR1 and UBR2 ubiquitin E3 ligases.Protein science : a publication of the Protein Society · 2025Article
- Cancer therapy and cachexia.The Journal of clinical investigation · 2025Review
- The role of UBR2 in triple-negative breast cancer and its implications for immune checkpoint blockade therapy.Discover oncology · 2025Article
- Calcium Handling Machinery and Sarcomere Assembly are Impaired Through Multipronged Mechanisms in Cancer Cytokine-Induced Cachexia.Journal of cachexia, sarcopenia and muscle · 2025Article
- Revealing the Mechanism of Protein Degradation in Postmortem Meat: The Role of Phosphorylation and Ubiquitination.Foods (Basel, Switzerland) · 2025Article
- Macrophage polarization: molecular mechanisms, disease implications, and targeted therapeutic strategies.Frontiers in immunology · 2025Review
- IFNα/JAK/STAT1 Axis-Induced FBXO4 Modulates Muscle Cell Differentiation via β-Catenin Degradation in Dermatomyositis.Journal of inflammation research · 2025Article
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Authors and funding
12 authors at 4 institutions in 2 countries.
Funding
Abstract
Cancer cachexia is a lethal metabolic syndrome featuring muscle wasting with preferential loss of fast-twitching muscle mass through an undefined mechanism. Here, we show that cancer induces muscle wasting by selectively degrading myosin heavy chain (MHC) subtypes IIb and IIx through E3 ligase UBR2-mediated ubiquitylation. Induction of MHC loss and atrophy in C2C12 myotubes and mouse tibialis anterior (TA) by murine cancer cells required UBR2 up-regulation by cancer. Genetic gain or loss of UBR2 function inversely altered MHC level and muscle mass in TA of tumor-free mice. UBR2 selectively interacted with and ubiquitylated MHC-IIb and MHC-IIx through its substrate recognition and catalytic domain, respectively, in C2C12 myotubes. Elevation of UBR2 in muscle of tumor-bearing or free mice caused loss of MHC-IIb and MHC-IIx but not MHC-I and MHC-IIa or other myofibrillar proteins, including α-actin, troponin, tropomyosin, and tropomodulin. Muscle-specific knockout of UBR2 spared KPC tumor-bearing mice from losing MHC-IIb and MHC-IIx, fast-twitching muscle mass, cross-sectional area, and contractile force. The rectus abdominis (RA) muscle of patients with cachexia-prone cancers displayed a selective reduction of MHC-IIx in correlation with higher UBR2 levels. These data suggest that UBR2 is a regulator of MHC-IIb/IIx essential for cancer-induced muscle wasting, and that therapeutic interventions can be designed by blocking UBR2 up-regulation by cancer.
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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.