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Identification and functional characterization of p130Cas as a substrate of protein tyrosine phosphatase nonreceptor 14

Oncogene volume 32, pages 2087–2095 (2013)Cite this article

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Abstract

Protein tyrosine phosphatase nonreceptor type 14 (PTPN14) is frequently mutated in a variety of human cancers. However, the cell signaling pathways regulated by PTPN14 largely remain to be elucidated. Here, we identify a list of potential substrates of PTPN14 using a phospho-proteomic approach. We show that p130 Crk-associated substrate (p130Cas) is a direct substrate of PTPN14 and that PTPN14 specifically regulates p130Cas phosphorylation at tyrosine residue 128 (Y128) in colorectal cancer (CRC) cells. We engineered CRC cells homozygous for a p130Cas Y128F knock-in mutant and found that these cells exhibit significantly reduced migration and colony formation, impaired anchorage-independent growth, slower xenograft tumor growth in nude mice and have decreased phosphorylation of AKT. Furthermore, we demonstrate that SRC phosphorylates p130Cas Y128 and that CRC cell lines harboring high levels of pY128Cas are more sensitive to SRC family kinase inhibitor Dasatinib. These findings suggest that p130Cas Y128 phosphorylation may be exploited as a predictive marker for Dasatinib response in cancer patients. In aggregate, our studies reveal a novel signaling pathway that has an important role in colorectal tumorigenesis.

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Acknowledgements

We thank Yueting Chen for excellent technical assistance, Drs Susann Brady-Kalnay, Hua Luo and CK Qu for helpful discussions, and Anthony Scott for critical reading of the manuscript. This research was supported by grants from the National Institutes of Health Grant R01-CA127590, R01-HG004722 and a pilot grant from the Case Comprehensive Cancer Center.

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Authors and Affiliations

  1. Department of Genetics, School of Medicine, Case Western Reserve University, Cleveland, OH, USA

    P Zhang, C Wang & Z Wang

  2. Case Comprehensive Cancer Center, School of Medicine, Case Western Reserve University, Cleveland, OH, USA

    P Zhang, C Wang, L Beard, S D Markowitz & Z Wang

  3. Cell Signaling Technology Inc., Danvers, MA, USA

    A Guo, A Possemato & R D Polakiewicz

  4. Department of Medicine, Case Medical Center, School of Medicine, Case Western Reserve University, Cleveland, OH, USA

    L Beard & S D Markowitz

  5. Genomic Medicine Institute, Cleveland Clinic Foundation, Cleveland, OH, USA

    Z Wang

  6. Department of Microbiology and Molecular Biology, School of Medicine, Case Western Reserve University, Cleveland, OH, USA

    C Carlin

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  1. P Zhang
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Zhang, P., Guo, A., Possemato, A. et al. Identification and functional characterization of p130Cas as a substrate of protein tyrosine phosphatase nonreceptor 14. Oncogene 32, 2087–2095 (2013). https://doi.org/10.1038/onc.2012.220

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