ArticleNature chemical biology2025
Targeting Smurf1 to block PDK1-Akt signaling in KRAS-mutated colorectal cancer.
Article in Nature chemical biology, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
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Who cites it
22 citing papers in PubMed.
- Upregulation of LTF promotes left-sided colorectal cancer development via activating PI3K/AKT pathway.Cell adhesion & migration · 2026Article
- SETDB1 cooperates with the CRL4B complex to promote colorectal cancer tumorigenesis by disrupting circadian rhythm.Oncogene · 2026Article
- Post-translational modifications in metabolic reprogramming: implications for metabolic therapy and immunotherapy in cancer.Signal transduction and targeted therapy · 2026Review
- Neddylation: from regulatory mechanisms to clinical implications in cancer.Journal of advanced research · 2026Review
- Sensory nerve-derived signaling coordinates oropharyngeal structural organization that supports suckling and vocalization in neonatal mice.Nature communications · 2026Article
- Phosphorylation-dependent STAMBP drives the progression of pancreatic ductal adenocarcinoma by deubiquitinating and stabilizing BAG3.Cell death and differentiation · 2026Article
- Targeting WFS1 overcomes KRASNPJ precision oncology · 2026Article
- EXOSC4 as a novel regulator of neddylation in acute myeloid leukemia.Scientific reports · 2026Article
- The Many Faces of SetDB1.Epigenomes · 2026Review
- UBE2M as a bridge spanning neddylation and cell cycle regulation in colorectal adenocarcinoma.Experimental & molecular medicine · 2026Article
- Decoding neddylation in malignancies: molecular mechanisms, biological functions, therapeutic resistance, and clinical potential.Cell death & disease · 2026Review
- PSMC5 Orchestrates an Immunosuppressive Niche and Metastasis in Colorectal Cancer via SMURF1-Mediated K11-Linked Ubiquitination of METTL14.International journal of biological sciences · 2026Article
- Phosphoinositide-dependent kinase 1 (PDK1) in cancer: molecular insights and therapeutic strategies.Frontiers in chemistry · 2026Review
- The role of neddylation in colorectal cancer and its therapeutic potential.Discover oncology · 2025Review
- [Role of the TGFZhong nan da xue xue bao. Yi xue ban = Journal of Central South University. Medical sciences · 2025Review
- Therapeutic targeting of post-translational modifications in ovarian cancer: mechanisms and clinical applications.Journal of ovarian research · 2025Review
- Exploration of purine metabolism-related genes in the development of osteoporosis by integrated analyses and experiments.European journal of medical research · 2025Article
- C1QTNF1-AS1/miR-346 axis suppresses osteosarcoma progression via dual inhibition of LDHA/PDK1-mediated Warburg effect.BMC cancer · 2025Article
- Anti-tumor efficacy of RAF/MEK inhibitor VS6766 in KRAS-mutated colorectal cancer cells.Cancer chemotherapy and pharmacology · 2025Article
- FGF-Mediated Axon Guidance: Role of Downstream Signaling Pathways in Cytoskeletal Control.Cells · 2025Review
Corrections and comments
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Authors and funding
21 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The phosphoinositide 3-kinase (PI3K)-Akt axis is one of the most frequently activated pathways and is demonstrated as a therapeutic target in Kirsten rat sarcoma viral oncogene homolog (KRAS)-mutated colorectal cancer (CRC). Targeting the PI3K-Akt pathway has been a challenging undertaking through the decades. Here we unveiled an essential role of E3 ligase SMAD ubiquitylation regulatory factor 1 (Smurf1)-mediated phosphoinositide-dependent protein kinase 1 (PDK1) neddylation in PI3K-Akt signaling and tumorigenesis. Upon growth factor stimulation, Smurf1 immediately triggers PDK1 neddylation and the poly-neural precursor cell expressed developmentally downregulated protein 8 (poly-Nedd8) chains recruit methyltransferase SET domain bifurcated histone lysine methyltransferase 1 (SETDB1). The cytoplasmic complex of PDK1 assembled with Smurf1 and SETDB1 (cCOMPASS) consisting of PDK1, Smurf1 and SETDB1 directs Akt membrane attachment and T308 phosphorylation. Smurf1 deficiency dramatically reduces CRC tumorigenesis in a genetic mouse model. Furthermore, we developed a highly selective Smurf1 degrader, Smurf1-antagonizing repressor of tumor 1, which exhibits efficient PDK1-Akt blockade and potent tumor suppression alone or combined with PDK1 inhibitor in KRAS-mutated CRC. The findings presented here unveil previously unrecognized roles of PDK1 neddylation and offer a potential strategy for targeting the PI3K-Akt pathway and KRAS mutant cancer therapy.
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