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

Estrada, Charlene LU ; Mirabel-Ortega, Liliana ; Méry, Laurence ; Dingli, Florent ; Besse, Laetitia ; Messaoudi, Cedric ; Loew, Damarys ; Pouponnot, Celio ; Bertolotto, Corine and Eychène, Alain , et al. (2022) In Communications Biology 5. p.1-13
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... (More)
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. (Less)
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publishing date
type
Contribution to journal
publication status
published
in
Communications Biology
volume
5
article number
101
pages
1 - 13
publisher
Nature Publishing Group
external identifiers
  • pmid:35091687
  • scopus:85123873284
ISSN
2399-3642
DOI
10.1038/s42003-022-03049-w
language
English
LU publication?
no
id
e042f857-4166-4848-bd64-4fe4afc6651b
date added to LUP
2022-03-28 14:18:03
date last changed
2025-10-14 11:45:48
@article{e042f857-4166-4848-bd64-4fe4afc6651b,
  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.}},
  author       = {{Estrada, Charlene and Mirabel-Ortega, Liliana and Méry, Laurence and Dingli, Florent and Besse, Laetitia and Messaoudi, Cedric and Loew, Damarys and Pouponnot, Celio and Bertolotto, Corine and Eychène, Alain and Druillennec, Sabine}},
  issn         = {{2399-3642}},
  language     = {{eng}},
  pages        = {{1--13}},
  publisher    = {{Nature Publishing Group}},
  series       = {{Communications Biology}},
  title        = {{MITF activity is regulated by a direct interaction with RAF proteins in melanoma cells}},
  url          = {{http://dx.doi.org/10.1038/s42003-022-03049-w}},
  doi          = {{10.1038/s42003-022-03049-w}},
  volume       = {{5}},
  year         = {{2022}},
}