P85\u03b2 regulates autophagic degradation of AXL to activate oncogenic signaling

Ling Rao,Rakesh Sharma,Lydia W T Cheung,Gordon B Mills,Chao Gu,Annie N Y Cheung,Xinran Li,Chloe C Y Fung,Dong Zhang,Victor C Y Mak,Yuan Zhou,George L Tipoe,Yiling Lu

doi:10.1038/s41467-020-16061-7

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.

Highlights

PIK3R2 encodes the p85β regulatory subunit of phosphatidylinositol 3-kinase and is frequently amplified in cancers
We showed that p85β but not p85α regulated the autophagylysosomal machinery to promote AXL protein stabilization and downstream signaling (Fig. 7e)
We demonstrated that AXL was ubiquitinated by TRIM2, which had not been demonstrated to target any receptor tyrosine kinases (RTKs)

Summary

Discussion

AXL is overexpressed in multiple cancer types, including ovarian cancer, causing malignant phenotypes and a poor prognosis[39,40,41]. Genomic aberrations in AXL are relatively rare in cancers It appears that AXL is primarily regulated at the levels of the promoter[42,43,44] and protein stability[12,45,46,47]. Combined mutation of the two residues was not additive It remains to be examined whether S526 alters the binding capacity of optineurin to ubiquitin. The other optineurin phosphorylation site we investigated is S513, which did not alter the effect of p85β on AXL. Studies have shown that S513 alone does not appear to regulate ubiquitin binding[24,27] but that S513 together with S473 may mediate mitophagy by promoting the recruitment and retention of optineurin on damaged mitochondria[24,27].

A66 TGX-221

Findings

Methods