p85β regulates autophagic degradation of AXL to activate oncogenic signaling

Proposed model of the mechanism underlying the oncogenicity of p85β

Rao et al. (2020) Nat Commun. CC BY 4.0

Rao L, Mak VCY, Zhou Y, Zhang D, Li X, Fung CCY, Sharma R, Gu C, Lu Y, Tipoe GL, Cheung ANY, Mills GB, Cheung LWT.

Nat Commun.

May 08, 2020

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.

Last updated: July 28, 2020