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

P Zhang1, A Guo, A Possemato

  • 1Department of Genetics, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA.

Oncogene
|June 20, 2012
PubMed

Insights

Protein tyrosine phosphatase nonreceptor type 14 (PTPN14) regulates p130 Crk-associated substrate (p130Cas) phosphorylation at Y128 in colorectal cancer. This pathway impacts tumor growth and may predict response to Dasatinib therapy.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Cell Signaling

Background:

  • Protein tyrosine phosphatase nonreceptor type 14 (PTPN14) is frequently altered in human cancers.
  • The specific cell signaling pathways regulated by PTPN14 are not fully understood.
  • Understanding PTPN14's role is crucial for developing targeted cancer therapies.

Purpose of the Study:

  • To identify direct substrates of PTPN14.
  • To elucidate the role of PTPN14 in colorectal cancer (CRC) tumorigenesis.
  • To investigate the therapeutic potential of targeting the PTPN14-p130Cas axis.

Main Methods:

  • Phospho-proteomic analysis to identify PTPN14 substrates.
  • Generation of p130Cas Y128F knock-in CRC cell lines.
  • Assessment of cell migration, colony formation, and anchorage-independent growth.
  • Xenograft tumor growth studies in nude mice.
  • Analysis of AKT and SRC phosphorylation.
  • Sensitivity assays with SRC family kinase inhibitor Dasatinib.

Main Results:

  • p130 Crk-associated substrate (p130Cas) was identified as a direct PTPN14 substrate.
  • PTPN14 regulates p130Cas phosphorylation at tyrosine 128 (Y128) in CRC cells.
  • p130Cas Y128F mutant cells showed reduced migration, colony formation, anchorage-independent growth, and slower tumor growth.
  • SRC family kinases phosphorylate p130Cas at Y128.
  • CRC cells with high pY128Cas levels are more sensitive to Dasatinib.

Conclusions:

  • PTPN14 directly dephosphorylates p130Cas at Y128, impacting CRC cell behavior and tumorigenesis.
  • p130Cas Y128 phosphorylation is regulated by SRC kinases.
  • p130Cas Y128 phosphorylation serves as a potential predictive biomarker for Dasatinib response in cancer patients.
  • A novel signaling pathway involving PTPN14 and p130Cas in colorectal tumorigenesis has been revealed.

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