Signal-regulated activation of serum response factor is mediated by changes in actin dynamics.
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.
Sotiropoulos
A
A
Transcription Laboratory, Imperial Cancer Research Fund Laboratories, London, United Kingdom.
Gineitis
D
D
Copeland
J
J
Treisman
R
R
D016475:3T3 Cells; D000199:Actins / Q000378:metabolism*; D000818:Animals; D019556:COS Cells; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D003599:Cytoskeleton / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005434:Flow Cytometry; D019204:GTP-Binding Proteins / Q000378:metabolism; D005786:Gene Expression Regulation / Q000502:physiology; D048031:JNK Mitogen-Activated Protein Kinases; D054461:Lim Kinases; D048670:MAP Kinase Kinase 4; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1; D020929:Mitogen-Activated Protein Kinase Kinases; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000378:metabolism*; D010766:Phosphorylation; D011108:Polymers; D011494:Protein Kinases / Q000378:metabolism; D026362:Serum Response Factor; D015398:Signal Transduction / Q000502:physiology*; D014158:Transcription, Genetic / Q000502:physiology; D016335:Zinc Fingers / Q000502:physiology; D020742:rhoA GTP-Binding Protein
D000199:Actins; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D011108:Polymers; D026362:Serum Response Factor; D011494:Protein Kinases; D054461:Lim Kinases; C515893:Limk1 protein, mouse; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048670:MAP Kinase Kinase 4; D020929:Mitogen-Activated Protein Kinase Kinases; D019204:GTP-Binding Proteins; D020742:rhoA GTP-Binding Protein