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.

Synergistic Anti-Tumour Effect of Syk Inhibitor and Olaparib in Squamous Cell Carcinoma: Roles of Syk in EGFR Signalling and PARP1 Activation

“…Notably, non-selective SFK inhibitor PP2 (10 µM) decreased the phosphorylation of c-Src, Lyn, Syk, and EGFR ( Figure 1B). Because PP2 also reduced EGFR phosphorylation, we suggest there is a feedback loop to control EGFR activation through SFKs as previously reported in fibroblasts [23], breast [23,24], and colon cancer cells [25] in a transactivation manner. All these findings suggested that Syk is a signal molecule for EGFR, and its activation is downstream of SFKs.…”

Expressions of 10 genes as candidate predictors of recurrence in stage�III colon cancer patients receiving adjuvant oxaliplatin‑based chemotherapy

“…Both CA12 and HMGCS2 are considered to be potential targets for cancer treatment. Of the remaining 8 genes, MS4A12 (30) and PTPRO (31) have been documented to be involved in the epidermal growth factor signaling pathway in CRC. TPI1 has been detected as an auto-antibody in the sera of CRC patients (32).…”

EGFR expression in patients with stage III colorectal cancer after adjuvant chemotherapy and on cancer cell function

“…Subsequently, the cells were washed with PBS, fixed with methanol, and then stained with 0.5% crystal violet. Colonies were photographed and counted using Image J software [ 35 ].…”