Oncotarget

Research Papers:

Regulation of paxillin-p130-PI3K-AKT signaling axis by Src and PTPRT impacts colon tumorigenesis

Yiqing Zhao, Anthony Scott, Peng Zhang, Yujun Hao, Xiujing Feng, Saigopal Somasundaram, Ahmad M. Khalil, Joseph Willis _ and Zhenghe Wang

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Oncotarget. 2017; 8:48782-48793. https://doi.org/10.18632/oncotarget.10654

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Abstract

Yiqing Zhao1,2,*, Anthony Scott1,2,*, Peng Zhang1,2, Yujun Hao1,2, Xiujing Feng1,2, Saigopal Somasundaram1, Ahmad M. Khalil1,2, Joseph Willis3 and Zhenghe Wang1,2

1Department of Genetics and Genome Sciences, Case Medical Center and Case Western Reserve University, Cleveland, Ohio 44106, USA

2Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio 44106, USA

3Department of Pathology, Case Medical Center and Case Western Reserve University, Cleveland, Ohio 44106, USA

*These authors have contributed equally to this work

Correspondence to:

Joseph Willis, email: Joseph.Willis@Case.edu

Zhenghe Wang, email: zxw22@case.edu

Keywords: PTPRT, paxillin, Src, colorectal cancer

Received: April 05, 2016    Accepted: June 03, 2016    Published: July 18, 2016

ABSTRACT

Protein tyrosine phosphatase receptor T (PTPRT) is frequently mutated in a variety of human cancers including colorectal cancer. Here we report that PTPRT knockout increases the size of mouse colon tumors in the Apcmin+/- genetic background, suggesting that inactivation of PTPRT promotes tumor progression. We previously demonstrated that PTPRT dephosphorylates paxillin at tyrosine-Y88 residue. Consistently, phosphorylation of Y88 paxillin (pY88) is up-regulated in colon tumors derived from Apcmin+/- Ptprt-/- mice. An important downstream effector of pY88 paxillin is the oncogene Akt. Here, we show that pY88 paxillin impacts the Akt pathway by regulating the interaction between p130cas and the p85 regulatory subunit of PI3-Kinase. Additionally, while pY88 paxillin is a substrate of the tumor suppressor phosphatase PTPRT, the corresponding kinase has not been previously identified. In this study, we demonstrate that the oncogenic kinase Src directly phosphorylates paxillin at Y88. Moreover, colorectal cancer cells that express high levels of pY88 paxillin are sensitive to dasatinib treatment, suggesting that pY88 paxillin may serve as a predictive biomarker for Src family kinase inhibitors.


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