Raf Inhibitors Target Ras Spatiotemporal Dynamics

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• 作者：Kwang-jin Cho¹ ; Rinshi  ; S. Kasai² ; Jin-Hee Park¹ ; Sravanthi Chigurupati¹ ; Sonja  ; J. Heidorn⁴ ; Dharini van  ; der  ; Hoeven¹ ; Sarah  ; J. Plowman¹ ; Akihiro Kusumi² ; ³ ; Richard Marais⁴ ; ^{richard.marais@icr.ac.uk} ; John  ; F. Hancock¹ ; ^{john.f.hancock@uth.tmc.edu}
• 刊名：Current Biology
• 出版年：2012
• 出版时间：5 June, 2012
• 年：2012
• 卷：22
• 期：11
• 页码：945-955
• 全文大小：1670 K

文摘

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Summary

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 of 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 dimers and p110¦Á 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.