Cookies on this website
We use cookies to ensure that we give you the best experience on our website. If you click 'Continue' we'll assume that you are happy to receive all cookies and you won't see this message again. Click 'Find out more' for information on how to change your cookie settings.

The oncogenic D816V mutation of the KIT receptor is well characterized in systemic mastocytosis and acute myeloid leukemia. Although KITD816V has been found in melanoma, its function and involvement in this malignancy is not understood. Here we show that KITD816V 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 KITD816V in melanoma and provided a rationale for the heightened SRC inhibitor sensitivity in KITD816V transformed cells.Implications: This study demonstrates that an oncogenic tyrosine kinase mutant, KITD816V, can alter the transcriptional program of the transcription factor MITF in melanoma Mol Cancer Res; 15(9); 1265-74. ©2017 AACR.

Original publication

DOI

10.1158/1541-7786.MCR-17-0149

Type

Journal article

Journal

Mol Cancer Res

Publication Date

09/2017

Volume

15

Pages

1265 - 1274

Keywords

Animals, Cell Line, Tumor, Cell Proliferation, Drosophila, HEK293 Cells, Humans, Melanoma, Melanoma, Experimental, Mice, Microphthalmia-Associated Transcription Factor, Phosphorylation, Proto-Oncogene Proteins c-kit, Signal Transduction, Skin Neoplasms, Transfection, Zebrafish, src-Family Kinases