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.

• MeSH
• HT29 Cells MeSH
• Caco-2 Cells MeSH
• Quinazolines pharmacology   MeSH
• Epidermal Growth Factor pharmacology   MeSH
• ErbB Receptors antagonists & inhibitors   metabolism   MeSH
• Phosphorylation MeSH
• HCT116 Cells MeSH
• HEK293 Cells MeSH
• Protein Kinase Inhibitors pharmacology   MeSH
• Humans MeSH
• MAP Kinase Signaling System MeSH
• RNA, Messenger genetics   metabolism   MeSH
• Cell Line, Tumor MeSH
• Colonic Neoplasms drug therapy   enzymology   genetics   pathology   MeSH
• Proto-Oncogene Proteins c-cbl metabolism   MeSH
• Signal Transduction MeSH
• src-Family Kinases metabolism   MeSH
• Receptor-Like Protein Tyrosine Phosphatases, Class 3 biosynthesis   genetics   metabolism   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH