Protein tyrosine phosphatase PTPN3 inhibits lung cancer cell proliferation and migration by promoting EGFR endocytic degradation

Abstract

Epidermal growth factor receptor (EGFR) regulates multiple signaling cascades essential for cell proliferation, growth and differentiation. Using a genetic approach, we found that Drosophila FERM and PDZ domain-containing protein tyrosine phosphatase, dPtpmeg, negatively regulates border cell migration and inhibits the EGFR/Ras/mitogen-activated protein kinase signaling pathway during wing morphogenesis. We further identified EGFR pathway substrate 15 (Eps15) as a target of dPtpmeg and its human homolog PTPN3. Eps15 is a scaffolding adaptor protein known to be involved in EGFR endocytosis and trafficking. Interestingly, PTPN3-mediated tyrosine dephosphorylation of Eps15 promotes EGFR for lipid raft-mediated endocytosis and lysosomal degradation. PTPN3 and the Eps15 tyrosine phosphorylation-deficient mutant suppress non-small-cell lung cancer cell growth and migration in vitro and reduce lung tumor xenograft growth in vivo. Moreover, depletion of PTPN3 impairs the degradation of EGFR and enhances proliferation and tumorigenicity of lung cancer cells. Taken together, these results indicate that PTPN3 may act as a tumor suppressor in lung cancer through its modulation of EGFR signaling.

EZH2 Modifies Sunitinib Resistance in Renal Cell Carcinoma by Kinome Reprogramming

“…5E). Both DAB2IP and PTPN3 are tumor suppressors that inhibit oncogenic signaling pathways such as RAS/MAPK and PI3K/AKT (37–40). In contrast, the PTK2 gene, which encodes the oncogenic kinase FAK, has decreased EZH2 binding in resistant cells that increases again upon EZH2 depletion (Fig.…”

On the move: endocytic trafficking in cell migration

“…Thus, Bif-1 is able to suppress breast cancer cell migration by promoting EGFR degradation through the regulation of endosome maturation [38]. The protein tyrosine phosphatase PTPN3, which was reported to inhibit border cell migration [39], likewise promotes EGFR degradation thereby inhibiting lung cancer cell migration. By dephosphorylating the endocytic factor Eps15, PTPN3 promotes lipid raft-mediated endocytosis of EGFR leading to its lysosomal degradation [39].…”

“…The protein tyrosine phosphatase PTPN3, which was reported to inhibit border cell migration [39], likewise promotes EGFR degradation thereby inhibiting lung cancer cell migration. By dephosphorylating the endocytic factor Eps15, PTPN3 promotes lipid raft-mediated endocytosis of EGFR leading to its lysosomal degradation [39]. In addition, a screen for new regulators of EGFR endocytosis in human HBL100 breast cancer cells recently identified annexin A2, an adapter protein with several interaction partners.…”

PTPN 3 acts as a tumor suppressor and boosts TGF ‐β signaling independent of its phosphatase activity

“…PTPN3 directly catalyzes Y1173 dephosphorylation of EGFR and cooperates with tyrosine kinase inhibitor (TKI) to inhibit breast cancer progression (Ma et al , ). In lung cancer, PTPN3 dephosphorylates Eps15 to promote EGFR degradation, thereby inhibiting lung cancer cell proliferation and migration (Li et al , ). Somatic mutations in PTPN3 are found in human colon cancers, suggesting a loss of its tumor suppressor activity (Wang et al , ).…”