Muscle-specific signaling mechanism that links actin dynamics to serum response factor.
Myocardin and the myocardin-related transcription factors (MRTFs) MRTF-A and MRTF-B are coactivators for serum response factor (SRF), which regulates genes involved in cell proliferation, migration, cytoskeletal dynamics, and myogenesis. MRTF-A has been shown to translocate to the nucleus and activate SRF in response to Rho signaling and actin polymerization. Previously, we described a muscle-specific actin-binding protein named striated muscle activator of Rho signaling (STARS) that also activates SRF through a Rho-dependent mechanism. Here we show that STARS activates SRF by inducing the nuclear translocation of MRTFs. The STARS-dependent nuclear import of MRTFs requires RhoA and actin polymerization, and the actin-binding domain of STARS is necessary and sufficient for this activity. A knockdown of endogenous STARS expression by using small interfering RNA significantly reduced SRF activity in differentiated C2C12 skeletal muscle cells and cardiac myocytes. The ability of STARS to promote the nuclear localization of MRTFs and SRF-mediated transcription provides a potential muscle-specific mechanism for linking changes in actin dynamics and sarcomere structure with striated muscle gene expression.
Kuwahara
Koichiro
K
Department of Molecular Biology, University of Texas Southwestern Medical Center at Dallas, 6000 Harry Hines Blvd., Dallas, TX 75390, USA.
Barrientos
Tomasa
T
Pipes
G C Teg
GC
Li
Shijie
S
Olson
Eric N
EN
D000199:Actins / Q000378:metabolism*; D021581:Active Transport, Cell Nucleus / Q000502:physiology; D000818:Animals; D002460:Cell Line; D002467:Cell Nucleus / Q000737:chemistry / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000032:analysis / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D051379:Mice; D008840:Microfilament Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D024510:Muscle Development / Q000235:genetics / Q000502:physiology*; D018485:Muscle Fibers, Skeletal / Q000187:drug effects / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism; D015514:Oncogene Proteins, Fusion / Q000032:analysis / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics / Q000494:pharmacology; D026362:Serum Response Factor / Q000378:metabolism*; D015398:Signal Transduction; D015534:Trans-Activators / Q000378:metabolism; D014157:Transcription Factors / Q000032:analysis / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000502:physiology*; D020742:rhoA GTP-Binding Protein / Q000378:metabolism; D000099251:Myocardin
D000199:Actins; D004268:DNA-Binding Proteins; D008840:Microfilament Proteins; D009687:Nuclear Proteins; D015514:Oncogene Proteins, Fusion; D034741:RNA, Small Interfering; D026362:Serum Response Factor; D015534:Trans-Activators; D014157:Transcription Factors; D020742:rhoA GTP-Binding Protein; D000099251:Myocardin; C464441:ABRA protein, human; C431575:MRTFA protein, human; C478036:MRTFB protein, human