Stabilization of C-RAF:KSR1 complex by DiRas3 reduces availability of C-RAF for dimerization with B-RAF
| Autor: | Maciej Dobrzyński, Angela Baljuls, Walter Kolch, Nora Rauch, Jens Rauch |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
Proto-Oncogene Proteins B-raf
rho GTP-Binding Proteins 0301 basic medicine MAPK/ERK pathway Intracellular Space Tumour suppressor DiRas3 Biology KSR1 PARP Proto-Oncogene Proteins p21(ras) Mice 03 medical and health sciences RAF dimerization Ras binding domain Animals c-Raf Cell Proliferation Poly(ADP-ribose) polymerase Protein Stability Kinase Cell Biology Cell biology Proto-Oncogene Proteins c-raf Cell Transformation Neoplastic 030104 developmental biology Ras-induced transformation Kinase suppressor of Ras Biochemistry Multiprotein Complexes NIH 3T3 Cells DIRAS3 Pyruvate kinase type M2 Protein Multimerization Protein Kinases Protein Binding Subcellular Fractions |
| Popis: | 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. Science Foundation Ireland German Research Foundation |
| Databáze: | OpenAIRE |
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