Identification and functional characterization of paxillin as a target of protein tyrosine phosphatase receptor T

Yiqing Zhao, Xiaodong Zhang, Kishore Guda, Earl Lawrence, Qun Sun, Toshio Watanabe, Yoichiro Iwakura, Masahide Asano, Lanlan Wei, Zhirong Yang, Weiping Zheng, Dawn Dawson, Joseph Willis, Sanford D. Markowitz, Masanobu Satake, Zhenghe Wang

Research output: Contribution to journalArticlepeer-review

58 Citations (Scopus)

Abstract

Protein tyrosine phosphatase receptor-type T (PTPRT) is the most frequently mutated tyrosine phosphatase in human cancers. However, the cell signaling pathways regulated by PTPRT largely remain to be elucidated. Here, we show that paxillin is a direct substrate of PTPRT and that PTPRT specifically regulates paxillin phosphorylation at tyrosine residue 88 (Y88) in colorectal cancer (CRC) cells. Weengineered CRC cells homozygous for a paxillin Y88F knock-in mutant and found that these cells exhibit significantly reduced cell migration and impaired anchorage-independent growth, fail to form xenograft tumors in nude mice, and have decreased phosphorylation of p130CAS, SHP2, and AKT. PTPRT knockout mice that we generated exhibit increased levels of colonic paxillin phosphorylation at residue Y88 and are highly susceptible to carcinogen azoxymethane-induced colon tumor, providing critical in vivo evidence that PTPRT normally functions as a tumor suppressor. Moreover, similarly increased paxillinpY88 is also found as a common feature of human colon cancers. These studies reveal an important signalingpathway that plays a critical role in colorectal tumorigenesis.

Original languageEnglish
Pages (from-to)2592-2597
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume107
Issue number6
DOIs
Publication statusPublished - 2010 Feb 9

Keywords

  • Colorectal cancer

ASJC Scopus subject areas

  • General

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