title: Stabilization of C-RAF:KSR1 complex by DiRas3 reduces availability of C-RAF for dimerization with B-RAF.
abstract: RAF family kinases are central components of the Ras-RAF-MEK-ERK cascade. Dimerization is a key mechanism of RAF activation in response to physiological, pathological and pharmacological signals. It is mediated by a dimer interface region in the RAF kinase domain that is also conserved in KSR, a scaffolding protein that binds RAF, MEK and ERK. The regulation of RAF dimerization is incompletely understood. Especially little is known about the molecular mechanism involved in the selection of the dimerization partner. Previously, we reported that Ras-dependent binding of the tumour suppressor DiRas3 to C-RAF inhibits the C-RAF:B-RAF heterodimerization. Here we show that DiRas3 binds to KSR1 independently of its interaction with activated Ras and RAF. Our data also suggest that depending on the local stoichiometry between DiRas3 and oncogenic Ras, DiRas3 can either enhance homodimerization of KSR1 or recruit KSR1 to the Ras:C-RAF complex and thereby reduce the availability of C-RAF for binding to B-RAF. This mechanism, which is shared between A-RAF and C-RAF, may be involved in the regulation of Ras12V-induced cell transformation by DiRas3.
authors.affiliation: Systems Biology Ireland, University College Dublin, Dublin 4, Ireland; Boehringer-Ingelheim Pharma, Birkendorfer Strasse 65, 88400 Biberach an der Riss, Germany. Electronic address: angela.baljuls@gmail.com.
authors.forename: Angela
authors.initials: A
authors.lastname: Baljuls
authors.affiliation: Systems Biology Ireland, University College Dublin, Dublin 4, Ireland.
authors.forename: Maciej
authors.initials: M
authors.lastname: Dobrzyński
authors.affiliation: Systems Biology Ireland, University College Dublin, Dublin 4, Ireland.
authors.forename: Jens
authors.initials: J
authors.lastname: Rauch
authors.affiliation: Systems Biology Ireland, University College Dublin, Dublin 4, Ireland.
authors.forename: Nora
authors.initials: N
authors.lastname: Rauch
authors.affiliation: Systems Biology Ireland, University College Dublin, Dublin 4, Ireland; Conway Institute of Biomolecular & Biomedical Research, University College Dublin, Dublin 4, Ireland; School of Medicine, University College Dublin, Belfield, Dublin 4, Ireland.
authors.forename: Walter
authors.initials: W
authors.lastname: Kolch
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic; D042541:Intracellular Space / Q000378:metabolism; D051379:Mice; D046912:Multiprotein Complexes / Q000378:metabolism*; D041681:NIH 3T3 Cells; D011485:Protein Binding; D011494:Protein Kinases / Q000378:metabolism*; D055503:Protein Multimerization; D055550:Protein Stability; D048493:Proto-Oncogene Proteins B-raf / Q000378:metabolism*; D019908:Proto-Oncogene Proteins c-raf / Q000378:metabolism*; D016283:Proto-Oncogene Proteins p21(ras) / Q000378:metabolism; D013347:Subcellular Fractions / Q000378:metabolism; D020741:rho GTP-Binding Proteins / Q000378:metabolism*
chemical_list: C117386:DIRAS3 protein, human; D046912:Multiprotein Complexes; D011494:Protein Kinases; C097199:KSR-1 protein kinase; D048493:Proto-Oncogene Proteins B-raf; D019908:Proto-Oncogene Proteins c-raf; C501009:HRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras); D020741:rho GTP-Binding Proteins
keywords: KSR1; RAF dimerization; Ras-induced transformation; Tumour suppressor DiRas3