Signal-Regulated Activation of Serum Response Factor Is Mediated by Changes in Actin Dynamics

Abstract

Serum response factor (SRF) regulates transcription of many serum-inducible and muscle-specific genes. Using a functional screen, we identified LIM kinase-1 as a potent activator of SRF. We show that SRF activation by LIM kinase-1 is dependent on its ability to regulate actin treadmilling. LIM kinase activity is not essential for SRF activation by serum, but signals depend on alterations in actin dynamics. Studies with actin-binding drugs, the actin-specific C2 toxin, and actin overexpression demonstrate that G-actin level controls SRF. Regulation of actin dynamics is necessary for serum induction of a subset of SRF target genes, including vinculin, cytoskeletal actin, and srf itself, and also suffices for their activation. Actin treadmilling provides a convergence point for both serum- and LIM kinase-1-induced signaling to SRF.

Activation of the c-fos enhancer by the Erk MAP kinase pathway through two sequence elements: the c-fos AP-1 and p62TCF sites

“…We found that the FAP1 site had no e ect on activated RhoA-V14 induction of the c-fos enhancer suggesting that Rho does not act through this site (data not shown). The direct mechanism of Rho induction of the SRE is unclear, however it was recently found that Rho and LIM kinase control of actin treadmilling and the control of free actin concentrations in the cells was critical for Rho and LIM kinase activation of the SRE (Sotiropoulos et al, 1999). In an additional pathway, increased calcium concentrations can also activate the SRE independently of the TCF site through a CaMK dependent pathway (Miranti et al, 1995).…”

“…Rho activation of the SRE requires SRF but the mechanism is unknown (Hill et al, 1995). Recently it was found that rho and LIM kinase regulation of actin treadmilling were critical to a pathway leading to SRE activation (Sotiropoulos et al, 1999).…”

5q– myelodysplastic syndromes: chromosome 5q genes direct a tumor-suppression network sensing actin dynamics

“…Alone or in combination with other transcription factors, SRF has a central role in controlling transcriptional responses to growth factors and other external stimuli (Posern and Treisman, 2006). Over the past two decades, studies have shown that SRF regulates the expression of numerous genes associated with cytoskeletal remodeling, including the b-actin gene (Sotiropoulos et al, 1999;Posern and Treisman, 2006). Rho family members and their actin-nucleating effectors, including Rho-activated mDia1, are strong activators of SRF-mediated gene expression Sahai et al, 1998;Sotiropoulos et al, 1999;Tominaga et al, 2000;Copeland and Treisman, 2002).…”

SRF is a nuclear repressor of Smad3-mediated TGF-β signaling

“…SRF is also activated in response to various stimuli, including serum, growth factors and intracellular calcium-regulating agents (Treisman, 1994). SRF is regulated by changes in actin dynamics to promote transcription of vinculin and actin, both necessary for the cytoskeletal changes essential to motility and invasion (Sotiropoulos et al, 1999). However, little is known of its implication in tumorigenesis.…”