| Summary: | The oncogenic D816V mutation of the KIT receptor is well characterized in systemic mastocytosis and acute myeloid leukemia. Although KIT<sup>D816V</sup> has been found in melanoma, its function and involvement in this malignancy is not understood. Here we show that KIT<sup>D816V</sup> 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<sup>D816V</sup> in melanoma and provided a rationale for the heightened SRC inhibitor sensitivity in KITD816V transformed cells. <br/><br/>Implications: This study demonstrates that an oncogenic tyrosine kinase mutant, KIT-D816V, can alter the transcriptional program of the transcription factor MITF in melanoma.
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