Stabilization of C-RAF:KSR1 complex by DiRas3 reduces availability of C-RAF for dimerization with B-RAF

Title: Stabilization of C-RAF:KSR1 complex by DiRas3 reduces availability of C-RAF for dimerization with B-RAF
Authors: Baljuls, Angela
Dobrzyński, Maciej
Rauch, Jens
Rauch, Nora
Kolch, Walter
Permanent link: http://hdl.handle.net/10197/9157
Date: Oct-2016
Online since: 2018-01-10T13:26:50Z
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.
Funding Details: Science Foundation Ireland
Type of material: Journal Article
Publisher: Elsevier
Journal: Cellular Signalling
Volume: 28
Issue: 10
Start page: 1451
End page: 1462
Copyright (published version): 2016 Elsevier
Keywords: RAF dimerizationKSR1Tumour suppressor DiRas3Ras-induced transformationKinase suppressor of RasRas binding domainPyruvate kinase type M2PARPPoly(ADP-ribose) polymerase
DOI: 10.1016/j.cellsig.2016.06.019
Language: en
Status of Item: Peer reviewed
Appears in Collections:Conway Institute Research Collection
SBI Research Collection
Medicine Research Collection

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