Skp2-dependent ubiquitination and activation of LKB1 is essential for cancer cell survival under energy stress.

LKB1 is activated by forming a heterotrimeric complex with STRAD and MO25. Recent studies suggest that LKB1 has pro-oncogenic functions, besides acting as a tumor suppressor. How the LKB1 activity is maintained and how LKB1 regulates cancer development are largely unclear. Here we show that K63-linked LKB1 polyubiquitination by Skp2-SCF ...
ubiquitin ligase is critical for LKB1 activation by maintaining LKB1-STRAD-MO25 complex integrity. We further demonstrate that oncogenic Ras acts upstream of Skp2 to promote LKB1 polyubiquitination by activating Skp2-SCF ubiquitin ligase. Moreover, Skp2-mediated LKB1 polyubiquitination is required for energy-stress-induced cell survival. We also detected overexpression of Skp2 and LKB1 in late-stage hepatocellular carcinoma (HCC), and their overexpression predicts poor survival outcomes. Finally, we show that Skp2-mediated LKB1 polyubiquitination is important for HCC tumor growth in vivo. Our study provides new insights into the upstream regulation of LKB1 activation and suggests a potential target, the Ras/Skp2/LKB1 axis, for cancer therapy.
Mesh Terms:
AMP-Activated Protein Kinase Kinases, AMP-Activated Protein Kinases, Adaptor Proteins, Vesicular Transport, Aged, Animals, Calcium-Binding Proteins, Cell Survival, Female, Humans, Liver Neoplasms, Male, Mice, Nude, Middle Aged, Protein Serine-Threonine Kinases, Retrospective Studies, S-Phase Kinase-Associated Proteins, Stress, Physiological, Ubiquitination, Xenograft Model Antitumor Assays, ras Proteins
Mol Cell
Date: Mar. 19, 2015
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