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Article Dans Une Revue Communications Biology Année : 2022

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

Résumé

Abstract 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.
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Dates et versions

hal-03844566 , version 1 (21-11-2022)

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Charlène Estrada, Liliana Mirabal-Ortega, Laurence Méry, Florent Dingli, Laetitia Besse, et al.. MITF activity is regulated by a direct interaction with RAF proteins in melanoma cells. Communications Biology, 2022, 5 (1), pp.101. ⟨10.1038/s42003-022-03049-w⟩. ⟨hal-03844566⟩
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