MITF activity is regulated by a direct interaction with RAF proteins in melanoma cells

The MITF transcription factor and the RAS/RAF/MEK/ERK pathway are two interconnected main players in melanoma. Understanding how MITF activity is regulated represents a key question since its dynamic modulation is involved in the phenotypic plasticity of melanoma cells and their resistance to therapy. By investigating the role of ARAF in NRAS-driven mouse melanoma through mass spectrometry experiments followed by a functional siRNA-based screen, we unexpectedly identified MITF as a direct ARAF partner. Interestingly, this interaction is conserved among the RAF protein kinase family since BRAF/MITF and CRAF/MITF complexes were also observed in the cytosol of NRAS-mutated mouse melanoma cells. The interaction occurs through the kinase domain of RAF proteins. Importantly, endogenous BRAF/MITF complexes were also detected in BRAF-mutated human melanoma cells. RAF/MITF complexes modulate MITF nuclear localization by inducing an accumulation of MITF in the cytoplasm, thus negatively controlling its transcriptional activity. Taken together, our study highlights a new level of regulation between two major mediators of melanoma progression, MITF and the MAPK/ERK pathway, which appears more complex than previously anticipated. The MITF transcription factor directly binds to the kinase domain of RAF kinases, including ARAF, BRAF and CRAF in melanoma cells. RAF/MITF complex promotes cytoplasmic accumulation of MITF and thus negatively regulates its transcriptional activity.

Automated summary

The MITF transcription factor directly interacts with RAF kinases, including ARAF, BRAF and CRAF, in melanoma cells. This interaction negatively regulates MITF activity by promoting its accumulation in the cytoplasm.