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; Lydia W.T. Cheung

doi:10.1038/s41467-020-16061-7

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, Lydia W.T. Cheung

Genomic Medicine

Research output: Contribution to journal › Article › peer-review

16 Scopus citations

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.

Original language	English (US)
Article number	2291
Journal	Nature communications
Volume	11
Issue number	1
DOIs	https://doi.org/10.1038/s41467-020-16061-7
State	Published - Dec 1 2020

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

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@article{937502603fbc446fb62cda408225a09e,

title = "p85β regulates autophagic degradation of AXL to activate oncogenic signaling",

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.",

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

note = "Funding Information: This study was supported by Hong Kong Research Grants Council (17111618) to L.W.C. We thank the RPPA Core Facility (funded by NCI #CA016672) of the MD Anderson Cancer Center (Houston, TX) and the Faculty Core Facility of the LKS Faculty of Medicine HKU for the help with confocal microscopy. G.B.M. is supported by a kind gift from the Adelson Medical Research Foundation, the Ovarian Cancer Research Foundation, The Breast Cancer Research Foundation, The Komen Foundation SAC110052, and NCI grants CA217685, CA217842, and CA098258. We also thank Professor Axel Ullrich (Max Planck Institute of Biochemistry, Germany) for generously providing the AXL plasmids and Professor Heike Allgayer (University of Heidelberg, Germany) for the human AXL gene promoter. Publisher Copyright: {\textcopyright} 2020, The Author(s).",

year = "2020",

month = dec,

day = "1",

doi = "10.1038/s41467-020-16061-7",

language = "English (US)",

volume = "11",

journal = "Nature communications",

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T1 - p85β regulates autophagic degradation of AXL to activate oncogenic signaling

AU - Rao, Ling

AU - Mak, Victor C.Y.

AU - Zhou, Yuan

AU - Zhang, Dong

AU - Li, Xinran

AU - Fung, Chloe C.Y.

AU - Sharma, Rakesh

AU - Gu, Chao

AU - Lu, Yiling

AU - Tipoe, George L.

AU - Cheung, Annie N.Y.

AU - Mills, Gordon B.

AU - Cheung, Lydia W.T.

N1 - Funding Information: This study was supported by Hong Kong Research Grants Council (17111618) to L.W.C. We thank the RPPA Core Facility (funded by NCI #CA016672) of the MD Anderson Cancer Center (Houston, TX) and the Faculty Core Facility of the LKS Faculty of Medicine HKU for the help with confocal microscopy. G.B.M. is supported by a kind gift from the Adelson Medical Research Foundation, the Ovarian Cancer Research Foundation, The Breast Cancer Research Foundation, The Komen Foundation SAC110052, and NCI grants CA217685, CA217842, and CA098258. We also thank Professor Axel Ullrich (Max Planck Institute of Biochemistry, Germany) for generously providing the AXL plasmids and Professor Heike Allgayer (University of Heidelberg, Germany) for the human AXL gene promoter. Publisher Copyright: © 2020, The Author(s).

PY - 2020/12/1

Y1 - 2020/12/1

N2 - 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.

AB - 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.

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DO - 10.1038/s41467-020-16061-7

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SN - 2041-1723

VL - 11

JO - Nature communications

JF - Nature communications

IS - 1

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ER -

p85β regulates autophagic degradation of AXL to activate oncogenic signaling

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ASJC Scopus subject areas

MD Anderson CCSG core facilities

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