Journal
EMBO JOURNAL
Volume 27, Issue 23, Pages 3175-3185Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/emboj.2008.226
Keywords
G proteins; multi-site phosphorylation; RhoE; ROCK-I; stress fibres
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Funding
- CR-UK
- BBSRC
- Beit Memorial Fellowship for Medical Research
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The ROCK-I serine/threonine protein kinase mediates the effects of RhoA to promote the formation of actin stress fibres and integrin-based focal adhesions. ROCK-I phosphorylates the unconventional G-protein RhoE on multiple N- and C-terminal sites. These phosphorylation events stabilise RhoE, which functions to antagonise RhoA-induced stress fibre assembly. Here, we provide a molecular explanation for multi-site phosphorylation of RhoE from the crystal structure of RhoE in complex with the ROCK-I kinase domain. RhoE interacts with the C-lobe alpha G helix of ROCK-I by means of a novel binding site remote from its effector region, positioning its N- and C-terminal proximal to the ROCK- I catalytic site. Disruption of the ROCK- I: RhoE interface abolishes RhoE phosphorylation, but has no effect on the ability of RhoE to disassemble stress fibres. In contrast, mutation of the RhoE effector region attenuates RhoE-mediated disruption of the actin cytoskeleton, indicating that RhoE exerts its inhibitory effects on ROCK- I through protein(s) binding to its effector region. We propose that ROCK-I phosphorylation of RhoE forms part of a feedback loop to regulate RhoA signalling.
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