探討PTPN3調控表皮生長因子受體(EGFR)內吞降解與抑制肺癌細胞進程之機轉

Abstract

表皮生長因子受體（EGFR）能調控多個不同的訊息傳遞路徑影響細胞的增殖，生長和分化。利用遺傳學篩選，我們發現果蠅中具有FERM和PDZ結構域的蛋白酪氨酸磷酸酶dPtpmeg，能負向調控果蠅邊界細胞遷移，抑制表皮生長因子受體下游的Ras/ MAPK訊號傳導影響果蠅翅膀發育。我們進一步確定了EGFR受質15（Eps15）為dPtpmeg和其人類同源蛋白PTPN3的共同受質。 Eps15是已知參與在表皮生長因子受體的內吞作用和運送接架蛋白。研究中發現有趣的是，由PTPN3所導致的Eps15酪氨酸去磷酸化能促進表皮生長因子受體的脂筏介導內吞作用和溶酶體降解。 PTPN3和Eps15酪氨酸磷酸化缺少突變能抑制非小細胞肺癌細胞的生長和細胞遷移的作用，並減少肺腫瘤異種移植的生長。此外，降低PTPN3會抑制表皮生長因子受體的降解，並增強擴散肺癌細胞和致瘤性。綜合上述結果，PTPN3可透過調控表皮生長因子受體訊息傳導，來抑制肺癌的進程，在肺癌中PTPN3扮演著腫瘤抑制的角色。

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/MAPK 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.