蛋白質酪氨酸的磷酸化在訊息傳遞路徑中是不可或缺的，異常的蛋白質酪氨酸磷酸化對於癌症的產生或是免疫失調等疾病皆扮演重要的角色。牛痘病毒H1相關去磷酸?(VHR)為第一個被發現的哺乳類雙特異性去磷酸?(DUSPs)。與典型雙特異性去磷酸?相比，VHR缺少促分裂素原活化蛋白激?(MAPK) 結合的區域，因此VHR對於MAPKs較不具調節作用。近來研究顯示上皮生長因子受體(EGFR)為VHR的直接受質，過度表現VHR會降低EGFR的磷酸化和訊息傳遞。VHR在非小細胞肺癌病人組織中表現顯著較低，說明了VHR表現的降低可能與非小細胞肺癌的發病有關聯。然而，VHR在非小細胞肺癌細胞的生物功能目前尚不清楚。我的初步實驗結果顯示，在trans-well 細胞爬行分析中，表達VHR會抑制細胞遷移。當加入EGFR inhibitor(Gefitinib)後，VHR仍然可以抑制細胞的遷移，說明了VHR可能透過EGFR訊息傳遞以外的路徑來調控細胞遷移。我們發現Src，樁蛋白(paxillin) 與集中附著點激?(focal adhesion kinase, FAK)是VHR的直接受質(substrate)。VHR會直接對FAK的酪胺酸397、576/7位置以及樁蛋白的酪胺酸31、118位置進行去磷酸化。VHR可能藉由調控整聯蛋白(integrin)相關的路徑來影響細胞爬行能力。 Protein tyrosine phosphorylation is important for signaling transduction pathways. Dysfunction of protein tyrosine phosphorylation may cause diseases from cancer to immune disorders in human beings. Vaccinia H1-related phosphatase (VHR) is the first identified mammalian dual-specificity phosphatase (DUSP). Unlike typical DUSPs, VHR lacks mitogen-activated protein kinase (MAPK)-binding domain, and shows poor activity against MAPKs. Recent study shows that epidermal growth factor receptor (EGFR) is a direct substrate of VHR, and that overexpression of VHR down-regulates EGFR phosphorylation and signaling. VHR expression is significantly lower in non-small cell lung cancer (NSCLC) tissues suggesting that down-regulation of VHR expression is involved in NSCLC pathogenesis. However, the biological functions of VHR in NSCLC cell is still not clear. My results showed that expression of VHR suppressed cell migration in Trans-well assays. In the presence of EGFR kinase inhibitor (Gefitinib), VHR still can suppress cell migration, indicating that VHR may regulate cell migration through molecules other than EGFR. I identified that Src, paxillin and focal adhesion kinase (FAK) are potential direct substrates of VHR. VHR dephosphorylated FAK on tyrosine 397, 576/577 residues and dephosphorylated paxillin on tyrosine 31 and 118 residues. VHR may affect cell migration through regulating integrin-dependent pathway to affect cell migration ability.
