2. Academic Validation
  3. Targeting Smurf1 to block PDK1-Akt signaling in KRAS-mutated colorectal cancer

Targeting Smurf1 to block PDK1-Akt signaling in KRAS-mutated colorectal cancer

  • Nat Chem Biol. 2024 Jul 22. doi: 10.1038/s41589-024-01683-5.
Zhiqiang Peng # 1 2 3,  Wei Fang # 1 2,  Bo Wu # 1,  Ming He # 4,  Shaohua Li # 1 2,  Jun Wei 2,  Yang Hao 1,  Lujia Jin 5,  Mingqiu Liu 1,  Xin Zhang 1,  Yange Wei 1,  Yingwei Ge 1,  Yinghua Wei 1 3,  Haili Qian 6,  Yangjun Zhang 1,  Junyi Jiang 1,  Zhijie Chang 3,  Yu Rao 7,  Xueli Zhang 8,  Chun-Ping Cui 9,  Lingqiang Zhang 10
Affiliations

Affiliations

  • 1 State Key Laboratory of Medical Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing, China.
  • 2 Shanghai Fengxian Central Hospital, The Third School of Clinical Medicine, Southern Medical University, Shanghai, China.
  • 3 School of Medicine, Tsinghua University, Beijing, China.
  • 4 MOE Key Laboratory of Protein Sciences, School of Pharmaceutical Sciences, MOE Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology, Tsinghua University, Beijing, China.
  • 5 Department of Gastrointestinal Surgery, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing, China.
  • 6 State Key Laboratory of Molecular Oncology, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
  • 7 MOE Key Laboratory of Protein Sciences, School of Pharmaceutical Sciences, MOE Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology, Tsinghua University, Beijing, China. yrao@tsinghua.edu.cn.
  • 8 Shanghai Fengxian Central Hospital, The Third School of Clinical Medicine, Southern Medical University, Shanghai, China. lejing1996@aliyun.com.
  • 9 State Key Laboratory of Medical Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing, China. cui_chunping2000@aliyun.com.
  • 10 State Key Laboratory of Medical Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing, China. zhanglq@nic.bmi.ac.cn.
  • # Contributed equally.
PMID: 39039255 DOI: 10.1038/s41589-024-01683-5
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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