Oncotarget

Research Papers:

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

Layka Abbasi Asbagh _, Iria Vazquez, Loredana Vecchione, Eva Budinska, Veerle De Vriendt, Maria Francesca Baietti, Mikhail Steklov, Bart Jacobs, Nicholas Hoe, Sharat Singh, Naga-Sailaja Imjeti, Pascale Zimmermann, Anna Sablina and Sabine Tejpar

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Oncotarget. 2014; 5:10070-10083. https://doi.org/10.18632/oncotarget.2458

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Abstract

Layka Abbasi Asbagh1,2,3, Iria Vazquez2,3, Loredana Vecchione1, Eva Budinska4, Veerle De Vriendt1, Maria Francesca Baietti2,3, Mikhail Steklov2,3, Bart Jacobs1, Nicholas Hoe5, Sharat Singh5, Naga-Sailaja Imjeti6,3, Pascale Zimmermann6,3, Anna Sablina2,3,*, Sabine Tejpar1,*

1Laboratory of Molecular Digestive Oncology, Department of Oncology, KU Leuven, Leuven, Belgium

2Laboratory for Mechanisms of Cell Transformation, VIB Center for the Biology of Disease, VIB, Belgium

3Center for Human Genetics, KU Leuven, Leuven, Belgium

4Institute of Biostatistics and Analyses, Faculty of Medicine, Masaryk University, Brno, Czech Republic

5Prometheus Laboratories, San Diego, CA, USA

6Centre de Recherche en Cancérologie de Marseille (CRCM), Inserm, U1068-CNRS UMR7258, Aix-Marseille Université, Institut Paoli-Calmettes, Marseille, France

*These authors contributed equally to this work

Correspondence to:

Anna Sablina, e-mail: Anna.Sablina@cme.vib-kuleuven.be

Keywords: EGFR, PTPRO, phosphatase, SRC kinase, EGFR inhibitor, colon cancer

Received: June 11, 2014     Accepted: September 12, 2014     Published: October 11, 2014

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.


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