KIT(D816V) Induces SRC-Mediated Tyrosine Phosphorylation of MITF and Altered Transcription Program in Melanoma

Bengt Phung, Julhash U Kazi, Alicia Lundby, Kristin Bergsteinsdottir, Jianmin Sun, Colin R Goding, Göran Jönsson, Jesper V Olsen, Eiríkur Steingrímsson, Lars Rönnstrand

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13 Citationer (Scopus)

Abstract

The oncogenic D816V mutation of the KIT receptor is well characterized in systemic mastocytosis and acute myeloid leukemia. Although KIT(D816V) has been found in melanoma, its function and involvement in this malignancy is not understood. Here we show that KIT(D816V) induces tyrosine phosphorylation of MITF through a triple protein complex formation between KIT, MITF, and SRC family kinases. In turn, phosphorylated MITF activates target genes that are involved in melanoma proliferation, cell-cycle progression, suppression of senescence, survival, and invasion. By blocking the triple protein complex formation, thus preventing MITF phosphorylation, the cells became hypersensitive to SRC inhibitors. We have therefore delineated a mechanism behind the oncogenic effects of KIT(D816V) in melanoma and provided a rationale for the heightened SRC inhibitor sensitivity in KIT(D816V) transformed cells.Implications: This study demonstrates that an oncogenic tyrosine kinase mutant, KIT(D816V), can alter the transcriptional program of the transcription factor MITF in melanoma Mol Cancer Res; 15(9); 1265-74. ©2017 AACR.

OriginalsprogEngelsk
TidsskriftMolecular cancer research : MCR
Vol/bind15
Udgave nummer9
Sider (fra-til)1265-1274
Antal sider10
ISSN1541-7786
DOI
StatusUdgivet - 2017

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