Deregulated Gab2 phosphorylation mediates aberrant AKT and STAT3 signaling upon PIK3R1 loss in ovarian cancer

Xinran Li; Victor C.Y. Mak; Yuan Zhou; Chao Wang; Esther S.Y. Wong; Rakesh Sharma; Yiling Lu; Annie N.Y. Cheung; Gordon B. Mills; Lydia W.T. Cheung

doi:10.1038/s41467-019-08574-7

Deregulated Gab2 phosphorylation mediates aberrant AKT and STAT3 signaling upon PIK3R1 loss in ovarian cancer

Xinran Li, Victor C.Y. Mak, Yuan Zhou, Chao Wang, Esther S.Y. Wong, Rakesh Sharma, Yiling Lu, Annie N.Y. Cheung, Gordon B. Mills, Lydia W.T. Cheung

Genomic Medicine

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

33 Scopus citations

Abstract

Copy number loss of PIK3R1 (p85α) most commonly occurs in ovarian cancer among all cancer types. Here we report that ovarian cancer cells manifest a spectrum of tumorigenic phenotypes upon knockdown of PIK3R1. PIK3R1 loss activates AKT and p110-independent JAK2/STAT3 signaling through inducing changes in the phosphorylation of the docking protein Gab2, thereby relieving the negative inhibition on AKT and promoting the assembly of JAK2/STAT3 signalosome, respectively. Additional mechanisms leading to AKT activation include enhanced p110α kinase activity and a decrease in PTEN level. PIK3R1 loss renders ovarian cancer cells vulnerable to inhibition of AKT or JAK2/STAT3. The combination of AKT and STAT3 inhibitors significantly increases the anti-tumor effect compared to single-agent treatments. Together, our findings provide a rationale for mechanism-based therapeutic approach that targets tumors with loss of PIK3R1.

Original language	English (US)
Article number	716
Journal	Nature communications
Volume	10
Issue number	1
DOIs	https://doi.org/10.1038/s41467-019-08574-7
State	Published - Dec 1 2019

ASJC Scopus subject areas

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

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@article{be2113c8056e40d1afe8f1040bfcd32e,

title = "Deregulated Gab2 phosphorylation mediates aberrant AKT and STAT3 signaling upon PIK3R1 loss in ovarian cancer",

abstract = "Copy number loss of PIK3R1 (p85α) most commonly occurs in ovarian cancer among all cancer types. Here we report that ovarian cancer cells manifest a spectrum of tumorigenic phenotypes upon knockdown of PIK3R1. PIK3R1 loss activates AKT and p110-independent JAK2/STAT3 signaling through inducing changes in the phosphorylation of the docking protein Gab2, thereby relieving the negative inhibition on AKT and promoting the assembly of JAK2/STAT3 signalosome, respectively. Additional mechanisms leading to AKT activation include enhanced p110α kinase activity and a decrease in PTEN level. PIK3R1 loss renders ovarian cancer cells vulnerable to inhibition of AKT or JAK2/STAT3. The combination of AKT and STAT3 inhibitors significantly increases the anti-tumor effect compared to single-agent treatments. Together, our findings provide a rationale for mechanism-based therapeutic approach that targets tumors with loss of PIK3R1.",

author = "Xinran Li and Mak, {Victor C.Y.} and Yuan Zhou and Chao Wang and Wong, {Esther S.Y.} and Rakesh Sharma and Yiling Lu 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 (#27103616) and National Natural Science Foundation of China (#81703066) to L.W.C.; NCI (1P50 CA217685-01, 1U01 CA217842-01), Ovarian Cancer Research Foundation, a kind gift from the Adelson Medical Research Foundation to G.B.M.; Health and Medical Research Fund, Hong Kong Special Administrative Region (#03143006) to A.N.C.; National Natural Science Foundation of China (#81772777) and Shanghai Pujiang Program (17PJ1401400) to C.W. The authors would like to thank the RPPA Core Facility and the Characterized Cell Line Core Facility (funded by NCI #CA016672) of the MD Anderson Cancer Center (Houston, TX) and Dr. Takashi Saito (RIKEN Center for Integrative Medical Science, Japan), Dr. Gen-sheng Feng (University of California San Diego, USA), Dr. Susan Meakin (University of Western Ontario, Canada) for generously providing the wild-type GAB2 plasmids. We also thank the Faculty Core Facility of the LKS Faculty of Medicine HKU for the help with flow cytometry and confocal microscopy.",

year = "2019",

month = dec,

day = "1",

doi = "10.1038/s41467-019-08574-7",

language = "English (US)",

volume = "10",

journal = "Nature communications",

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T1 - Deregulated Gab2 phosphorylation mediates aberrant AKT and STAT3 signaling upon PIK3R1 loss in ovarian cancer

AU - Li, Xinran

AU - Mak, Victor C.Y.

AU - Zhou, Yuan

AU - Wang, Chao

AU - Wong, Esther S.Y.

AU - Sharma, Rakesh

AU - Lu, Yiling

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 (#27103616) and National Natural Science Foundation of China (#81703066) to L.W.C.; NCI (1P50 CA217685-01, 1U01 CA217842-01), Ovarian Cancer Research Foundation, a kind gift from the Adelson Medical Research Foundation to G.B.M.; Health and Medical Research Fund, Hong Kong Special Administrative Region (#03143006) to A.N.C.; National Natural Science Foundation of China (#81772777) and Shanghai Pujiang Program (17PJ1401400) to C.W. The authors would like to thank the RPPA Core Facility and the Characterized Cell Line Core Facility (funded by NCI #CA016672) of the MD Anderson Cancer Center (Houston, TX) and Dr. Takashi Saito (RIKEN Center for Integrative Medical Science, Japan), Dr. Gen-sheng Feng (University of California San Diego, USA), Dr. Susan Meakin (University of Western Ontario, Canada) for generously providing the wild-type GAB2 plasmids. We also thank the Faculty Core Facility of the LKS Faculty of Medicine HKU for the help with flow cytometry and confocal microscopy.

PY - 2019/12/1

Y1 - 2019/12/1

N2 - Copy number loss of PIK3R1 (p85α) most commonly occurs in ovarian cancer among all cancer types. Here we report that ovarian cancer cells manifest a spectrum of tumorigenic phenotypes upon knockdown of PIK3R1. PIK3R1 loss activates AKT and p110-independent JAK2/STAT3 signaling through inducing changes in the phosphorylation of the docking protein Gab2, thereby relieving the negative inhibition on AKT and promoting the assembly of JAK2/STAT3 signalosome, respectively. Additional mechanisms leading to AKT activation include enhanced p110α kinase activity and a decrease in PTEN level. PIK3R1 loss renders ovarian cancer cells vulnerable to inhibition of AKT or JAK2/STAT3. The combination of AKT and STAT3 inhibitors significantly increases the anti-tumor effect compared to single-agent treatments. Together, our findings provide a rationale for mechanism-based therapeutic approach that targets tumors with loss of PIK3R1.

AB - Copy number loss of PIK3R1 (p85α) most commonly occurs in ovarian cancer among all cancer types. Here we report that ovarian cancer cells manifest a spectrum of tumorigenic phenotypes upon knockdown of PIK3R1. PIK3R1 loss activates AKT and p110-independent JAK2/STAT3 signaling through inducing changes in the phosphorylation of the docking protein Gab2, thereby relieving the negative inhibition on AKT and promoting the assembly of JAK2/STAT3 signalosome, respectively. Additional mechanisms leading to AKT activation include enhanced p110α kinase activity and a decrease in PTEN level. PIK3R1 loss renders ovarian cancer cells vulnerable to inhibition of AKT or JAK2/STAT3. The combination of AKT and STAT3 inhibitors significantly increases the anti-tumor effect compared to single-agent treatments. Together, our findings provide a rationale for mechanism-based therapeutic approach that targets tumors with loss of PIK3R1.

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JO - Nature communications

JF - Nature communications

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Deregulated Gab2 phosphorylation mediates aberrant AKT and STAT3 signaling upon PIK3R1 loss in ovarian cancer

Abstract

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MD Anderson CCSG core facilities

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