Role and regulation of STAT3 phosphorylation at Ser727 in melanocytes and melanoma cells

Abstract

The transcription factor signal transducer and activator of transcription 3 (STAT3) is constitutively activated through Tyr705 phosphorylation in most melanoma cells. In this study, the role and regulation of Ser727 phosphorylation in STAT3, another critical phosphorylation event, in melanoma cells and melanocytes were examined. Ser727 was constitutively phosphorylated in all of seven melanoma cell lines examined. Constitutive Ser727 phosphorylation was partially attenuated by U0126, an inhibitor of extracellular-regulated kinase (ERK) kinase (MEK). In WM39 cells containing STAT3 phosphorylated on Ser727 (pS-STAT3) but not STAT3 phosphorylated on Tyr705 (pY-STAT3), pS-STAT3 was localized mainly in the nucleus and U0126 treatment resulted in a decrease in nuclear pS-STAT3 and total nuclear STAT3 concomitant with an increase in total cytosolic STAT3. Blockade of STAT3 activity in WM39 cells by small interfering RNAs suppressed the growth of the cells. Melanocytes did not express pY-STAT3 but expressed low levels of pS-STAT3 in the nucleus. Upon treatment with 12-O-tetradecanoylphorbol-ester (TPA), a growth stimulator for melanocytes, nuclear pS-STAT3 and total nuclear STAT3 were increased, without affecting Tyr705 phosphorylation, concomitant with enhanced proliferative activity. These results indicate that Ser727 phosphorylation in melanoma cells is mediated in part by the MEK-ERK1/2 pathway and that it plays a crucial role in the nuclear translocation of STAT3 and growth in melanoma cells and melanocytes. Furthermore, immunohistochemical studies on specimens of primary lesions of acral lentiginous melanoma (ALM) revealed that Ser727 phosphorylation frequently precedes Tyr705 phosphorylation in the early stages of ALM progression. JSID AbstractsJournal of Dermatological ScienceVol. 69Issue 2Preview Full-Text PDF