Journal article
Raf Inhibitors Target Ras Spatiotemporal Dynamics
Current biology, Vol.22(11), pp.945-955
06/05/2012
DOI: 10.1016/j.cub.2012.03.067
PMID: 22560614
Abstract
Background: The lateral segregation of Ras proteins into transient plasma membrane nanoclusters is essential for high-fidelity signal transmission by the Ras mitogen-activated protein kinase (MAPK) cascade. In this spatially constrained signaling system, the dynamics of Ras nanocluster assembly and disassembly control MAPK signal output.
Results: We show here that BRaf inhibitors paradoxically activate CRaf and MAPK signaling in Ras transformed cells by profoundly dysregulating Ras nanocluster dynamics. Specifically, BRaf inhibitors selectively enhance the plasma membrane nanoclustering of oncogenic K-Ras and N-Ras but have no effect on H-Ras nanoclustering. Raf inhibitors are known to drive the formation of stable BRaf-CRaf and CRaf-CRaf dimers. Our results demonstrate that the presence of two Ras-binding domains in a single Raf dimer is sufficient and required to increase Ras nanoclustering, indicating that Raf dimers promote K- and N-Ras nanocluster formation by crosslinking constituent Ras proteins. Ras crosslinking increases the fraction cif K-Ras and N-Ras in their cognate nanoclusters, leading to an increase in MAPK output from the plasma membrane. Intriguingly, increased MAPK signaling in BRaf inhibited cells is accompanied by significantly decreased Akt activation. We show that this signal pathway crosstalk results from a novel mechanism of competition between stabilized Raf dinners and p110 alpha for recruitment to Ras nanoclusters.
Conclusions: Our findings reveal that BRaf inhibitors disrupt Ras nanocluster dynamics with significant, yet divergent, consequences for MAPK and PI3K signaling.
Details
- Title: Subtitle
- Raf Inhibitors Target Ras Spatiotemporal Dynamics
- Creators
- Kwang-jin Cho - The University of Texas Health Science Center at HoustonRinshi S. Kasai - Kyoto UniversityJin-Hee Park - The University of Texas Health Science Center at HoustonSravanthi Chigurupati - The University of Texas Health Science Center at HoustonSonja J. Heidorn - Institute of Cancer ResearchDharini van der Hoeven - The University of Texas Health Science Center at HoustonSarah J. Plowman - The University of Texas Health Science Center at HoustonAkihiro Kusumi - Kyoto UniversityRichard Marais - Institute of Cancer ResearchJohn F. Hancock - The University of Texas Health Science Center at Houston
- Resource Type
- Journal article
- Publication Details
- Current biology, Vol.22(11), pp.945-955
- DOI
- 10.1016/j.cub.2012.03.067
- PMID
- 22560614
- NLM abbreviation
- Curr Biol
- ISSN
- 0960-9822
- eISSN
- 1879-0445
- Publisher
- Elsevier
- Number of pages
- 11
- Grant note
- RP100483 / Cancer Prevention and Research Institute of Texas (CPRIT) 24115511 / Grants-in-Aid for Scientific Research; Ministry of Education, Culture, Sports, Science and Technology, Japan (MEXT); Japan Society for the Promotion of Science; Grants-in-Aid for Scientific Research (KAKENHI) World Premier International Research Center Initiative (WPI) of the Japanese government (MEXT) 19279 / Cancer Research UK
- Language
- English
- Date published
- 06/05/2012
- Academic Unit
- Oral Pathology, Radiology and Medicine; Dentistry Administration
- Record Identifier
- 9985157545802771
Metrics
1 Record Views