KIT^D816V induces SRC-mediated tyrosine phosphorylation of MITF and altered transcription program in melanoma

The oncogenic D816V mutation of the KIT receptor is well characterized in systemic mastocytosis and acute myeloid leukemia. Although KITD^816V has been found in melanoma, its function and involvement in this malignancy is not understood. Here we show that KITD^816V 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, cellcycle 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 KITD^816V in melanoma and provided a rationale for the heightened SRC inhibitor sensitivity in KITD^816V transformed cells. Implications: This study demonstrates that an oncogenic tyrosine kinase mutant, KITD^816V, can alter the transcriptional program of the transcription factor MITF in melanoma.