MITF activity is regulated by a direct interaction with RAF proteins in melanoma cells
(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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- author
- publishing date
- 2022
- 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
- 2022-04-21 18:33:17
@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}}, }