LIM kinase and Diaphanous cooperate to regulate serum response factor and actin dynamics.

Olivier Geneste,Richard Treisman,John W Copeland

doi:10.1083/jcb.200203126

Olivier Geneste, Richard Treisman + Show 1 more

Open Access

https://doi.org/10.1083/jcb.200203126

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Abstract

The small GTPase RhoA controls activity of serum response factor (SRF) by inducing changes in actin dynamics. We show that in PC12 cells, activation of SRF after serum stimulation is RhoA dependent, requiring both actin polymerization and the Rho kinase (ROCK)–LIM kinase (LIMK)–cofilin signaling pathway, previously shown to control F-actin turnover. Activation of SRF by overexpression of wild-type LIMK or ROCK-insensitive LIMK mutants also requires functional RhoA, indicating that a second RhoA-dependent signal is involved. This is provided by the RhoA effector mDia: dominant interfering mDia1 derivatives inhibit both serum- and LIMK-induced SRF activation and reduce the ability of LIMK to induce F-actin accumulation. These results demonstrate a role for LIMK in SRF activation, and functional cooperation between RhoA-controlled LIMK and mDia effector pathways.

Highlights

The Rho family of Ras-related GTPases are involved in the control of many cellular processes, including cytoskeletal organization, cell cycle control, and transformation, and transcriptional regulation
Because serum response factor (SRF) activation is dependent on alterations in actin dynamics, these results suggest that the ability of LIM kinases (LIMKs) to induce increases in F-actin will be dependent on mDia activity
ROCK-mediated activation of LIMK and phosphorylation of cofilin are required for serum-induced signaling to SRF in the PC12 neuronal cell line

Summary

Introduction

The Rho family of Ras-related GTPases are involved in the control of many cellular processes, including cytoskeletal organization, cell cycle control, and transformation, and transcriptional regulation (for reviews see Van Aelst and D’Souza-Schorey, 1997; Bishop and Hall, 2000). The Rho family GTPase RhoA controls the formation of actin structures by interacting with a set of effector proteins that includes the Rho kinases (ROCKs; known as ROKs), myosin light chain (MLC)* phosphatase, PI4-P 5-kinase, and the Diaphanous group of formin proteins (mDia proteins; for reviews see Kaibuchi et al, 1999; Amano et al, 2000). The ROCK kinases play several roles in RhoA-induced actin reorganization. They control actin filament bundling by phosphorylating MLC and inhibiting MLC phosphatase (Amano et al, 1996; Kimura et al, 1996); regulate synthesis of PI-4,5P, an important regulator.

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