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

Mol Cancer Res. 2017 Sep;15(9):1265-1274. doi: 10.1158/1541-7786.MCR-17-0149. Epub 2017 Jun 5.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

  • MITF protein, human
  • Microphthalmia-Associated Transcription Factor
  • Proto-Oncogene Proteins c-kit
  • src-Family Kinases