title: RAF1/BRAF dimerization integrates the signal from RAS to ERK and ROKα.
abstract: Downstream of growth factor receptors and of the guanine triphosphatase (GTPase) RAS, heterodimers of the serine/threonine kinases BRAF and RAF1 are critical upstream kinases and activators of the mitogen-activated protein kinase (MAPK) module containing the mitogen-activated and extracellular signal-regulated kinase kinase (MEK) and their targets, the extracellular signal-regulated kinase (ERK) family. Either direct or scaffold protein-mediated interactions among the components of the ERK module (the MAPKKKs BRAF and RAF1, MEK, and ERK) facilitate signal transmission. RAF1 also has essential functions in the control of tumorigenesis and migration that are mediated through its interaction with the kinase ROKα, an effector of the GTPase RHO and regulator of cytoskeletal rearrangements. We combined mutational and kinetic analysis with mathematical modeling to show that the interaction of RAF1 with ROKα is coordinated with the role of RAF1 in the ERK pathway. We found that the phosphorylated form of RAF1 that interacted with and inhibited ROKα was generated during the interaction of RAF1 with the ERK module. This mechanism adds plasticity to the ERK pathway, enabling signal diversification at the level of both ERK and RAF. Furthermore, by connecting ERK activation with the regulation of ROKα and cytoskeletal rearrangements by RAF1, this mechanism has the potential to precisely coordinate the proper timing of proliferation with changes in cell shape, adhesion, or motility.
authors.affiliation: Department of Microbiology, Immunology and Genetics, Max F. Perutz Laboratories, University of Vienna, Vienna, Austria.
authors.forename: Andrea
authors.identifier: http://orcid.org/0000-0001-9165-5368
authors.initials: A
authors.lastname: Varga
authors.affiliation: Department of Microbiology, Immunology and Genetics, Max F. Perutz Laboratories, University of Vienna, Vienna, Austria.
authors.forename: Karin
authors.identifier: http://orcid.org/0000-0002-3866-5695
authors.initials: K
authors.lastname: Ehrenreiter
authors.affiliation: Department of Microbiology, Immunology and Genetics, Max F. Perutz Laboratories, University of Vienna, Vienna, Austria.
authors.forename: Bertram
authors.identifier: http://orcid.org/0000-0003-1177-7109
authors.initials: B
authors.lastname: Aschenbrenner
authors.affiliation: Institute of Fundamental Technological Research, Polish Academy of Sciences, Warsaw, Poland.
authors.forename: Pawel
authors.initials: P
authors.lastname: Kocieniewski
authors.affiliation: Institute of Fundamental Technological Research, Polish Academy of Sciences, Warsaw, Poland.
authors.forename: Marek
authors.identifier: http://orcid.org/0000-0003-1215-3920
authors.initials: M
authors.lastname: Kochanczyk
authors.affiliation: Institute of Fundamental Technological Research, Polish Academy of Sciences, Warsaw, Poland.
authors.forename: Tomasz
authors.identifier: http://orcid.org/0000-0002-3488-2561
authors.initials: T
authors.lastname: Lipniacki
authors.affiliation: Department of Microbiology, Immunology and Genetics, Max F. Perutz Laboratories, University of Vienna, Vienna, Austria. manuela.baccarini@univie.ac.at.
authors.forename: Manuela
authors.identifier: http://orcid.org/0000-0002-3033-391X
authors.initials: M
authors.lastname: Baccarini
mesh_terms: D000818:Animals; D019556:COS Cells; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D004622:Embryo, Mammalian / Q000166:cytology; D004815:Epidermal Growth Factor / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism*; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D018345:Mice, Knockout; D011485:Protein Binding; D055503:Protein Multimerization; D048493:Proto-Oncogene Proteins B-raf / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D019908:Proto-Oncogene Proteins c-raf / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D015398:Signal Transduction; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism*; D054460:rho-Associated Kinases / Q000235:genetics / Q000378:metabolism*
chemical_list: D004815:Epidermal Growth Factor; D048493:Proto-Oncogene Proteins B-raf; D019908:Proto-Oncogene Proteins c-raf; D054460:rho-Associated Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D018631:ras Proteins