p85β regulates autophagic degradation of AXL to activate oncogenic signaling

Ling Rao, Victor C. Y. Mak, Yuan Zhou, Dong Zhang, Xinran Li, Chloe C. Y. Fung, Rakesh Sharma, Chao Gu, Yiling Lu, George L. Tipoe, Annie N. Y. Cheung, Gordon B. Mills and Lydia W. T. Cheung ()
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Ling Rao: The University of Hong Kong
Victor C. Y. Mak: The University of Hong Kong
Yuan Zhou: The University of Hong Kong
Dong Zhang: Oregon Health and Science University
Xinran Li: The University of Hong Kong
Chloe C. Y. Fung: The University of Hong Kong
Rakesh Sharma: The University of Hong Kong
Chao Gu: Fudan University
Yiling Lu: The University of Texas MD Anderson Cancer Center
George L. Tipoe: The University of Hong Kong
Annie N. Y. Cheung: The University of Hong Kong
Gordon B. Mills: Oregon Health and Science University
Lydia W. T. Cheung: The University of Hong Kong

Nature Communications, 2020, vol. 11, issue 1, 1-15

Abstract: Abstract PIK3R2 encodes the p85β regulatory subunit of phosphatidylinositol 3-kinase and is frequently amplified in cancers. The signaling mechanism and therapeutic implication of p85β are poorly understood. Here we report that p85β upregulates the protein level of the receptor tyrosine kinase AXL to induce oncogenic signaling in ovarian cancer. p85β activates p110 activity and AKT-independent PDK1/SGK3 signaling to promote tumorigenic phenotypes, which are all abolished upon inhibition of AXL. At the molecular level, p85β alters the phosphorylation of TRIM2 (an E3 ligase) and optineurin (an autophagy receptor), which mediate the selective regulation of AXL by p85β, thereby disrupting the autophagic degradation of the AXL protein. Therapeutically, p85β expression renders ovarian cancer cells vulnerable to inhibitors of AXL, p110, or PDK1. Conversely, p85β-depleted cells are less sensitive to these inhibitors. Together, our findings provide a rationale for pharmacological blockade of the AXL signaling axis in PIK3R2-amplified ovarian cancer.

Date: 2020
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DOI: 10.1038/s41467-020-16061-7

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