title: The tyrosine phosphatase PTPRO sensitizes colon cancer cells to anti-EGFR therapy through activation of SRC-mediated EGFR signaling.
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.
authors.affiliation: 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.
authors.forename: Layka Abbasi
authors.initials: LA
authors.lastname: Asbagh
authors.affiliation: Laboratory for Mechanisms of Cell Transformation, VIB Center for the Biology of Disease, VIB, Belgium. Center for Human Genetics, KU Leuven, Leuven, Belgium.
authors.forename: Iria
authors.initials: I
authors.lastname: Vazquez
authors.affiliation: Laboratory of Molecular Digestive Oncology, Department of Oncology, KU Leuven, Leuven, Belgium.
authors.forename: Loredana
authors.initials: L
authors.lastname: Vecchione
authors.affiliation: Institute of Biostatistics and Analyses, Faculty of Medicine, Masaryk University, Brno, Czech Republic.
authors.forename: Eva
authors.initials: E
authors.lastname: Budinska
authors.affiliation: Laboratory of Molecular Digestive Oncology, Department of Oncology, KU Leuven, Leuven, Belgium.
authors.forename: Veerle
authors.initials: V
authors.lastname: De Vriendt
authors.affiliation: Laboratory for Mechanisms of Cell Transformation, VIB Center for the Biology of Disease, VIB, Belgium. Center for Human Genetics, KU Leuven, Leuven, Belgium.
authors.forename: Maria Francesca
authors.initials: MF
authors.lastname: Baietti
authors.affiliation: Laboratory for Mechanisms of Cell Transformation, VIB Center for the Biology of Disease, VIB, Belgium. Center for Human Genetics, KU Leuven, Leuven, Belgium.
authors.forename: Mikhail
authors.initials: M
authors.lastname: Steklov
authors.affiliation: Laboratory of Molecular Digestive Oncology, Department of Oncology, KU Leuven, Leuven, Belgium.
authors.forename: Bart
authors.initials: B
authors.lastname: Jacobs
authors.affiliation: Prometheus Laboratories, San Diego, CA, USA.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Hoe
authors.affiliation: Prometheus Laboratories, San Diego, CA, USA.
authors.forename: Sharat
authors.initials: S
authors.lastname: Singh
authors.affiliation: 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.
authors.forename: Naga-Sailaja
authors.initials: NS
authors.lastname: Imjeti
authors.affiliation: 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.
authors.forename: Pascale
authors.initials: P
authors.lastname: Zimmermann
authors.affiliation: Laboratory for Mechanisms of Cell Transformation, VIB Center for the Biology of Disease, VIB, Belgium. Center for Human Genetics, KU Leuven, Leuven, Belgium.
authors.forename: Anna
authors.initials: A
authors.lastname: Sablina
authors.affiliation: Laboratory of Molecular Digestive Oncology, Department of Oncology, KU Leuven, Leuven, Belgium.
authors.forename: Sabine
authors.initials: S
authors.lastname: Tejpar
mesh_terms: D018938:Caco-2 Cells; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D004815:Epidermal Growth Factor / Q000494:pharmacology; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000077156:Gefitinib; D045325:HCT116 Cells; D057809:HEK293 Cells; D019073:HT29 Cells; D006801:Humans; D020935:MAP Kinase Signaling System; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D050721:Proto-Oncogene Proteins c-cbl / Q000378:metabolism; D011799:Quinazolines / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D054631:Receptor-Like Protein Tyrosine Phosphatases, Class 3 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D019061:src-Family Kinases / Q000378:metabolism*
chemical_list: D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D012333:RNA, Messenger; D004815:Epidermal Growth Factor; D050721:Proto-Oncogene Proteins c-cbl; C512478:EGFR protein, human; D066246:ErbB Receptors; D019061:src-Family Kinases; C516888:PTPRO protein, human; D054631:Receptor-Like Protein Tyrosine Phosphatases, Class 3; C067419:CBL protein, human; D000077156:Gefitinib