title: Protein arginine methyltransferase 5 regulates ERK1/2 signal transduction amplitude and cell fate through CRAF.
abstract: The RAS to extracellular signal-regulated kinase (ERK) signal transduction cascade is crucial to cell proliferation, differentiation, and survival. Although numerous growth factors activate the RAS-ERK pathway, they can have different effects on the amplitude and duration of the ERK signal and, therefore, on the biological consequences. For instance, nerve growth factor, which elicits a larger and more sustained increase in ERK phosphorylation in PC12 cells than does epidermal growth factor (EGF), stimulates PC12 cell differentiation, whereas EGF stimulates PC12 cell proliferation. Here, we show that protein arginine methylation limits the ERK1/2 signal elicited by particular growth factors in different cell types from various species. We found that this restriction in ERK1/2 phosphorylation depended on methylation of RAF proteins by protein arginine methyltransferase 5 (PRMT5). PRMT5-dependent methylation enhanced the degradation of activated CRAF and BRAF, thereby reducing their catalytic activity. Inhibition of PRMT5 activity or expression of RAF mutants that could not be methylated not only affected the amplitude and duration of ERK phosphorylation in response to growth factors but also redirected the response of PC12 cells to EGF from proliferation to differentiation. This additional level of regulation within the RAS pathway may lead to the identification of new targets for therapeutic intervention.
authors.affiliation: Mouse Models and Cancer Laboratory, Anatomy Pathology Department, Vall d'Hebron Research Institute, Barcelona 08035, Spain.
authors.forename: Pedro
authors.initials: P
authors.lastname: Andreu-Pérez
authors.forename: Rosaura
authors.initials: R
authors.lastname: Esteve-Puig
authors.forename: Carlos
authors.initials: C
authors.lastname: de Torre-Minguela
authors.forename: Marta
authors.initials: M
authors.lastname: López-Fauqued
authors.forename: Joan Josep
authors.initials: JJ
authors.lastname: Bech-Serra
authors.forename: Stephan
authors.initials: S
authors.lastname: Tenbaum
authors.forename: Elena R
authors.initials: ER
authors.lastname: García-Trevijano
authors.forename: Francesc
authors.initials: F
authors.lastname: Canals
authors.forename: Glenn
authors.initials: G
authors.lastname: Merlino
authors.forename: Matías A
authors.initials: MA
authors.lastname: Avila
authors.forename: Juan A
authors.initials: JA
authors.lastname: Recio
mesh_terms: D000818:Animals; D019556:COS Cells; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology*; D049109:Cell Proliferation; D002522:Chlorocebus aethiops; D004815:Epidermal Growth Factor / Q000378:metabolism / Q000494:pharmacology; D057809:HEK293 Cells; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology*; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics / Q000378:metabolism*; D020932:Nerve Growth Factor / Q000378:metabolism / Q000494:pharmacology; D016716:PC12 Cells; D010766:Phosphorylation / Q000187:drug effects / Q000502:physiology; D011496:Protein Methyltransferases / Q000235:genetics / Q000378:metabolism*; D011484:Protein-Arginine N-Methyltransferases; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics / Q000378:metabolism; D019908:Proto-Oncogene Proteins c-raf / Q000235:genetics / Q000378:metabolism*; D051381:Rats
chemical_list: C502240:NGF protein, human; D004815:Epidermal Growth Factor; D020932:Nerve Growth Factor; D011496:Protein Methyltransferases; C400529:PRMT5 protein, human; D011484:Protein-Arginine N-Methyltransferases; C482119:BRAF protein, human; C482123:Braf protein, rat; D048493:Proto-Oncogene Proteins B-raf; D019908:Proto-Oncogene Proteins c-raf; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3