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Oncotarget. 2014 Oct 30;5(20):10070-83.

The tyrosine phosphatase PTPRO sensitizes colon cancer cells to anti-EGFR therapy through activation of SRC-mediated EGFR signaling.

Author information

1
Laboratory of Molecular Digestive Oncology, Department of Oncology, KU Leuven, Leuven, Belgium. Laboratory for Mechanisms of Cell Transformation, VIB Center for the Biology of Disease, VIB, Belgium. Center for Human Genetics, KU Leuven, Leuven, Belgium.
2
Laboratory for Mechanisms of Cell Transformation, VIB Center for the Biology of Disease, VIB, Belgium. Center for Human Genetics, KU Leuven, Leuven, Belgium.
3
Laboratory of Molecular Digestive Oncology, Department of Oncology, KU Leuven, Leuven, Belgium.
4
Institute of Biostatistics and Analyses, Faculty of Medicine, Masaryk University, Brno, Czech Republic.
5
Prometheus Laboratories, San Diego, CA, USA.
6
Centre de Recherche en Cancérologie de Marseille (CRCM), Inserm, U1068-CNRS UMR7258, Aix-Marseille Université, Institut Paoli-Calmettes, Marseille, France. Center for Human Genetics, KU Leuven, Leuven, Belgium.

Abstract

Inappropriate activation of epidermal growth factor receptor (EGFR) plays a causal role in many cancers including colon cancer. The activation of EGFR by phosphorylation is balanced by receptor kinase and protein tyrosine phosphatase activities. However, the mechanisms of negative EGFR regulation by tyrosine phosphatases remain largely unexplored. Our previous results indicate that protein tyrosine phosphatase receptor type O (PTPRO) is down-regulated in a subset of colorectal cancer (CRC) patients with a poor prognosis. Here we identified PTPRO as a phosphatase that negatively regulates SRC by directly dephosphorylating Y416 phosphorylation site. SRC activation triggered by PTPRO down-regulation induces phosphorylation of both EGFR at Y845 and the c-CBL ubiquitin ligase at Y731. Increased EGFR phosphorylation at Y845 promotes its receptor activity, whereas enhanced phosphorylation of c-CBL triggers its degradation promoting EGFR stability. Importantly, hyperactivation of SRC/EGFR signaling triggered by loss of PTPRO leads to high resistance of colon cancer to EGFR inhibitors. Our results not only highlight the PTPRO contribution in negative regulation of SRC/EGFR signaling but also suggest that tumors with low PTPRO expression may be therapeutically targetable by anti-SRC therapies.

PMID:
25301722
PMCID:
PMC4259406
DOI:
10.18632/oncotarget.2458
[Indexed for MEDLINE]
Free PMC Article

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