STARS, a Striated Muscle Activator of Rho Signaling and Serum Response Factor-dependent Transcription

Changes in actin dynamics influence diverse cellular processes and couple the actin-based cytoskeleton to changes in gene transcription. Members of the Rho GTPase family regulate cytoskeletal organization by stimulating actin polymerization and stress fiber formation when activated by extracellular signaling. The transcriptional activity of serum response factor (SRF) is stimulated in response to changes in actin dynamics and Rho signaling, but the proteins that mediate this phenomenon have not been fully identified. We describe a novel, evolutionarily conserved actin-binding protein, called STARS (striated muscle activator ofRho signaling), that is expressed specifically in cardiac and skeletal muscle cells. STARS binds to the I-band of the sarcomere and to actin filaments in transfected cells, where it activates Rho-signaling events. STARS stimulates the transcriptional activity of SRF through a mechanism that requires actin binding and involves Rho GTPase activation. STARS provides a potential mechanism for specifically enhancing Rho-dependent transcription in muscle cells and for linking changes in actin dynamics to gene transcription. Changes in actin dynamics influence diverse cellular processes and couple the actin-based cytoskeleton to changes in gene transcription. Members of the Rho GTPase family regulate cytoskeletal organization by stimulating actin polymerization and stress fiber formation when activated by extracellular signaling. The transcriptional activity of serum response factor (SRF) is stimulated in response to changes in actin dynamics and Rho signaling, but the proteins that mediate this phenomenon have not been fully identified. We describe a novel, evolutionarily conserved actin-binding protein, called STARS (striated muscle activator ofRho signaling), that is expressed specifically in cardiac and skeletal muscle cells. STARS binds to the I-band of the sarcomere and to actin filaments in transfected cells, where it activates Rho-signaling events. STARS stimulates the transcriptional activity of SRF through a mechanism that requires actin binding and involves Rho GTPase activation. STARS provides a potential mechanism for specifically enhancing Rho-dependent transcription in muscle cells and for linking changes in actin dynamics to gene transcription. serum response factor MCM1, Agamous, Deficiens, and SRF differential product phosphate-buffered saline glutathioneS-transferase embryonic day bovine serum albumin tetramethylrhodamine isothiocyanate cytochalasin D latrunculin B guanine nucleotide exchange factor rapid amplification of cDNA ends The actin cytoskeleton influences diverse cellular processes, including motility, mitosis, contractility, cytokinesis, endocytosis, and secretion (1Burridge K. Chrzanowska-Wodnicka M. Annu. Rev. Cell Dev. Biol. 1996; 12: 463-518Crossref PubMed Scopus (1639) Google Scholar, 2Schmidt A. Hall M.N. Annu. Rev. Cell Dev. Biol. 1998; 14: 305-338Crossref PubMed Scopus (368) Google Scholar, 3Pantaloni D., Le Clainche C. Carlier M.F. Science. 2001; 292: 1502-1506Crossref PubMed Scopus (550) Google Scholar). Actin also participates in numerous transmembrane signaling systems by forming complexes with cell adhesion molecules and receptors (4Juliano R.L. Haskill S. J. Cell Biol. 1993; 120: 577-585Crossref PubMed Scopus (1523) Google Scholar, 5Calderwood D.A. Shattil S.J. Ginsberg M.H. J. Biol. Chem. 2000; 275: 22607-22610Abstract Full Text Full Text PDF PubMed Scopus (406) Google Scholar). In addition, actin has been implicated in the control of gene transcription through its direct association with chromatin-remodeling complexes (6Rando O.J. Zhao K. Crabtree G.R. Trends Cell Biol. 2000; 10: 92-97Abstract Full Text Full Text PDF PubMed Scopus (214) Google Scholar) and through indirect mechanisms mediated by changes in cytoskeletal actin dynamics (7Sotiropoulos A. Gineitis D. Copeland J. Treisman R. Cell. 1999; 98: 159-169Abstract Full Text Full Text PDF PubMed Scopus (572) Google Scholar). Actin exists in monomeric (G-actin) and polymerized (F-actin) forms. The distribution of actin between these two forms is tightly regulated and is influenced by numerous actin-binding proteins that control actin dynamics by severing (i.e. actin-depolymerizing factor/cofilin), cross-linking (i.e. α-actinin, tropomyosin), and capping (i.e. tropomodulin at the point ends and capZ at the Z-line) actin (8Cooper J.A. Schafer D.A. Curr. Opin. Cell Biol. 2000; 12: 97-103Crossref PubMed Scopus (262) Google Scholar). Members of the Rho GTPase family regulate cytoskeletal organization by stimulating actin polymerization and stress fiber formation when activated by extracellular signaling (9Ridley A.J. Hall A. Cell. 1992; 70: 389-399Abstract Full Text PDF PubMed Scopus (3785) Google Scholar). A number of Rho effector molecules, including Rho kinase, mDia, and phosphatidylinositol phosphate 5-kinase, also participate in cytoskeletal organization (10Kaibuchi K. Kuroda S. Amano M. Annu. Rev. Biochem. 1999; 68: 459-486Crossref PubMed Scopus (883) Google Scholar, 11Maekawa M. Ishizaki T. Boku S. Watanabe N. Fujita A. Iwamatsu A. Obinata T. Ohashi K. Mizuno K. Narumiya S. Science. 1999; 285: 895-898Crossref PubMed Scopus (1257) Google Scholar, 12Narumiya S. Ishizaki T. Watanabe N. FEBS Lett. 1997; 410: 68-72Crossref PubMed Scopus (326) Google Scholar, 13Yamamoto M. Hilgemann D.H. Feng S. Bito H. Ishihara H. Shibasaki Y. Yin H.L. J. Cell Biol. 2001; 152: 867-876Crossref PubMed Scopus (103) Google Scholar, 14Van Aelst L. D'Souza-Schorey C. Genes Dev. 1997; 11: 2295-2322Crossref PubMed Scopus (2080) Google Scholar). Recent studies showed that RhoA signaling stimulates the transcriptional activity of serum response factor (SRF)1 through a mechanism mediated by changes in actin dynamics (7Sotiropoulos A. Gineitis D. Copeland J. Treisman R. Cell. 1999; 98: 159-169Abstract Full Text Full Text PDF PubMed Scopus (572) Google Scholar, 15Mack C.P. Somlyo A.V. Hautmann M. Somlyo A.P. Owens G.K. J. Biol. Chem. 2001; 276: 341-347Abstract Full Text Full Text PDF PubMed Scopus (324) Google Scholar). SRF is a MADS-box transcription factor that regulates serum-inducible and muscle-specific gene expression by binding to a consensus sequence known a CArG box, CC(A/T)6GG (16Treisman R. Nature. 1995; 376: 468-469Crossref PubMed Scopus (30) Google Scholar, 17Treisman R. EMBO J. 1995; 14: 4905-4913Crossref PubMed Scopus (345) Google Scholar). Members of the myocyte enhancer factor-2 family of MADS-box transcription factors, which regulate muscle cell differentiation (18Black B.L. Olson E.N. Annu. Rev. Cell Dev. Biol. 1998; 14: 167-196Crossref PubMed Scopus (835) Google Scholar), are also stimulated by RhoA signaling (19Marinissen M.J. Chiariello M. Gutkind J.S. Genes Dev. 2001; 15: 535-553Crossref PubMed Scopus (148) Google Scholar). Consistent with a role in the activation of SRF and myocyte enhancer factor-2 transcription factors, Rho signaling has been shown to be required for muscle cell differentiation (20Takano H. Komuro I. Oka T. Shiojima I. Hiroi Y. Mizuno T. Yazaki Y. Mol. Cell. Biol. 1998; 18: 1580-1589Crossref PubMed Scopus (130) Google Scholar). Rho signaling has also been shown to activate members of the GATA family of transcription factors during cardiomyocyte hypertrophy (21Yanazume T. Hasegawa K. Wada H. Morimoto T. Abe M. Kawamura T. Sasayama S. J. Biol. Chem. 2001; 277: 8618-8625Abstract Full Text Full Text PDF PubMed Scopus (86) Google Scholar). In light of the requirement of Rho signaling during muscle cell differentiation and hypertrophy, it is tempting to speculate as to the existence of muscle-specific regulators of Rho signaling. Here, we describe a novel actin-binding protein, striated muscle activator of Rho signaling (STARS), identified in a differential cDNA screen for unknown genes expressed in the early embryonic heart. STARS is associated with the I-band of the sarcomere and with actin stress fibers in transfected cells. STARS contains a unique, evolutionarily conserved domain that stimulates SRF-dependent transcription through a mechanism that requires actin polymerization and Rho GTPase activation. These findings suggest that STARS acts as a muscle-specific transducer of cytoskeletal signals that stimulate Rho signaling, thereby activating SRF-dependent transcription. For subtractive screening by representational difference analysis, hearts and the region of the embryo dorsal to the heart, including the neural fold and the first three somites, were dissected from embryonic day (E)-8.25 mouse embryos. Total RNA was isolated from the heart and the dorsal embryonic region using TRIZOL (Invitrogen). mRNA was purified using a mRNA purification kit (Amersham Biosciences) and converted into double-strand cDNA by the Superscript choice system for cDNA synthesis (Invitrogen). For subtraction screening between heart (Tester) and other embryonic parts (Driver), we employed the representational difference analysis method described by Hubank and Schatz (22Hubank M. Schatz D.G. Methods Enzymol. 1999; 303: 325-349Crossref PubMed Scopus (97) Google Scholar). Briefly, the cDNA from both tissues was digested withDpnII and ligated with an R-linker (the annealed oligonucleotides were R-Bgl-12 (5′-GATCTGCGGTGA-3′) and R-Bgl-24 (5′-AGCACTCTCCAGCCTCTCACCGCA-3′)). Using R-Bgl-24 as primer, cDNA was amplified by PCR and digested with DpnII again. cDNA from the heart was purified by gel extraction and ligated with a J-linker (the annealed oligonucleotides were J-Bgl-12 (5′-GATCTGTTCATG-3′) and J-Bgl-24 (5′-ACCGACGTCGACTATCCATGAACA-3′)). Tester ligated with J-linker and Driver cDNAs (ratio 1:100) were hybridized at 67 °C for 20 h. PCR reactions were then performed by primer J-Bgl-24 to yield a PCR product referred to as DPI (differential product). DPI was digested with DpnII as a new tester and ligated with N-linker (the annealed oligonucleotides were N-Bgl-12 (5′-GATCTTTCCATCG-3′) andN-Bgl-24 (5′-AGGCAACTGTGCTATCCGAGGGAA-3′)).N-Linker-ligated DPI was hybridized with Driver (ratio 1:800) and amplified by PCR two times usingN-oligonucleotides as primer. Linkers for tester were replaced with J-oligonucleotides in the third round andN-oligonucleotides in the fourth round of hybridization. The final PCR products, referred to as DPIV, were cloned into the TA cloning vector (pGEMT-easy, Promega), and inserted DPIV fragments were amplified by PCR using N-Bgl-24 as primers to make two identical dot blots. One dot blot was hybridized with tester probe, and the other was hybridized with driver probe to confirm the differential expression of DPIV fragments. To obtain a full-length STARS cDNA, an E10.5 mouse heart cDNA library (Stratagene) was screened using a 342-bp cDNA fragment isolated by representational difference analysis. The longest positive clone contained a 375-amino acid open reading frame without a stop codon 5′ of the first methionine in the sequence. To further obtain 5′ sequences, adult mouse heart and skeletal muscle cDNA libraries (CLONTECH) were screened with a 400-bp cDNA fragment from the 5′ end of the longest cDNA as a probe. 5′-Rapid amplification of cDNA ends (5′-RACE) was also performed using the SMART 5′-RACE kit (CLONTECH) and the RLM first choice 5′-RACE kit (Ambion) following the manufacturer's instructions. 5′-rapid amplification of cDNA ends was performed with mRNA from human skeletal muscle (CLONTECH) and from mouse heart and skeletal muscle. There were no stop codons upstream of the first methionine. Northern blot analysis was performed using mouse and human multiple tissue Northern blots (CLONTECH). 32P-Labeled probes were prepared from a full-length mouse STARS cDNA and a partial human cDNA. Hybridizations were performed in (CLONTECH). RNA probes to the and the of the STARS cDNA were In was performed of mouse as described J. J.A. Dev. 1997; PubMed Scopus Google Scholar). STARS expression were using the expression vector which was to an RhoA and in were by Hall The contained the L. Olson E.N. J. Cell Biol. 1996; PubMed Scopus Google Scholar). The muscle contained of the first and the first ligated into the vector The contained of the CArG with as described L. J. Olson E.N. J. Biol. Chem. 2001; 276: Full Text Full Text PDF PubMed Scopus Google Scholar). was as an control for were isolated as described R.L. N. M. J. Olson E.N. EMBO J. 2001; PubMed Scopus Google Scholar). cells were in with bovine was to and were performed at using following the manufacturer's instructions. of for the and for D and were B in was and was to control were and and activity were were performed at three times with for For cells were with in in for and in for For in was were for at in bovine serum albumin in for cells and in serum in for cells were with first in in for at at was at a were and were isothiocyanate at a with without and blot analysis was performed as described J. Olson E.N. Mol. Cell. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). For cells were with of blots were performed with by with To blots were with for and to A cDNA the full-length STARS open reading frame was cloned into vector Biochem. PubMed Scopus Google Scholar). cells the expression were to an of and with for at was purified by using actin and were from was from Actin were performed as by and were by and was by using the full-length STARS to For and was purified from with We performed a differential cDNA screen for novel genes expressed in the mouse heart at but not in other of the embryo and potential heart genes were for in to confirm cardiac One of the cDNAs isolated in the screen a novel 375-amino acid that we to as striated of Rho signaling (STARS), it is expressed specifically in striated muscle where it binds actin and activates Rho GTPase The open reading frame of STARS not for genes an human by a gene A partial cDNA a was also identified in the number other genes were identified in the of the mouse and human with the potential to proteins with to the of STARS were also identified in and and Consistent with the cDNA subtraction STARS were by in specifically in the heart at STARS expression was in the heart and was also in skeletal muscle E10.5 not Northern analysis of adult tissues three STARS in mouse heart and skeletal muscle and two in these human tissues of multiple cDNAs a open reading frame with no for the we the multiple the of blot analysis of adult mouse heart with an a of to the of STARS with a STARS expressed in transfected cells. To the distribution of were with the STARS a and STARS showed a of The of STARS the both as by a partial with and that STARS is to the I-band of the In to I-band a of STARS to between A of STARS is in C. We also the of a STARS in transfected cells. STARS with which is by in a of cells, STARS was to the not To a was to we performed in actin In the of was contained in the and in the of was in the actin a positive purified was as was contained in the actin and In to with actin these These that STARS with actin and to actin polymerization polymerized actin and to To the actin binding region of were performed in cells transfected with STARS in shown in the and the conserved were to with A further to acid actin that the of STARS also not actin and an to with These that binding of STARS to actin requires two but by and Recent studies that of the actin cytoskeleton stimulates the transcriptional activity of SRF (7Sotiropoulos A. Gineitis D. Copeland J. Treisman R. Cell. 1999; 98: 159-169Abstract Full Text Full Text PDF PubMed Scopus (572) Google Scholar, 15Mack C.P. Somlyo A.V. Hautmann M. Somlyo A.P. Owens G.K. J. Biol. Chem. 2001; 276: 341-347Abstract Full Text Full Text PDF PubMed Scopus (324) Google Scholar). To STARS participate in a signaling between the cytoskeleton and the we the of which is regulated by SRF in muscle cells L. Olson E.N. Dev. Biol. 1997; PubMed Scopus Google C. Mol. Cell. Biol. 1997; PubMed Scopus Google Scholar), was to STARS stimulated the expression of an by in transfected cells of the CArG in the to the of SRF in this of SRF activity is not a of actin-binding as has no SRF activity not STARS also stimulated the muscle actin which is regulated by SRF C.P. Owens G.K. 1999; PubMed Scopus Google Scholar), and it activated to of the CArG and from the of the of STARS showed a direct between the to actin and to transcription and The conserved region of STARS was and to stimulate SRF as by the that was as as the full-length in activating To STARS stimulates SRF activity its actin we cells with cytochalasin D which actin polymerization T. Scopus Google Scholar), and latrunculin B which monomeric actin Cell Biol. 2000; PubMed Scopus Google Scholar). In cells, fragments of stress fibers were in the of not STARS activated In the of activity by with (7Sotiropoulos A. Gineitis D. Copeland J. Treisman R. Cell. 1999; 98: 159-169Abstract Full Text Full Text PDF PubMed Scopus (572) Google Scholar, 15Mack C.P. Somlyo A.V. Hautmann M. Somlyo A.P. Owens G.K. J. Biol. Chem. 2001; 276: 341-347Abstract Full Text Full Text PDF PubMed Scopus (324) Google Scholar). activation by activity in cells transfected with STARS These findings that transcriptional activation by STARS is mediated in by the actin The of and are to differential the of C. J. Biol. Chem. Full Text PDF PubMed Google Scholar), Cell Biol. 2000; PubMed Scopus Google Scholar). In light of the of RhoA to stimulate SRF activity by actin polymerization (7Sotiropoulos A. Gineitis D. Copeland J. Treisman R. Cell. 1999; 98: 159-169Abstract Full Text Full Text PDF PubMed Scopus (572) Google Scholar, 15Mack C.P. Somlyo A.V. Hautmann M. Somlyo A.P. Owens G.K. J. Biol. Chem. 2001; 276: 341-347Abstract Full Text Full Text PDF PubMed Scopus (324) Google Scholar), we the of a RhoA and STARS shown in STARS and RhoA activated the to and stimulated activity to Rho signaling is by the Rho which stress fiber formation M. Ishizaki T. Boku S. Watanabe N. Fujita A. Iwamatsu A. Obinata T. Ohashi K. Mizuno K. Narumiya S. Science. 1999; 285: 895-898Crossref PubMed Scopus (1257) Google Scholar), and which specifically RhoA Y. T. T. N. Narumiya S. J. Biol. Chem. 1992; Full Text PDF PubMed Google Scholar). of cells with with a expression the activity of STARS by and these suggest that STARS activation of transcription is mediated at in by a Rho-dependent STARS is a novel and evolutionarily conserved actin-binding expressed specifically in striated muscle. STARS to the sarcomere of and to actin stress fibers in transfected cells. of the actin cytoskeleton by STARS stimulates SRF-dependent transcription through a mechanism that involves RhoA signaling. STARS contains no and a new of actin-binding of STARS that are two that in to The of the actin binding between and STARS proteins that this activity has been evolutionarily also be that STARS with the actin cytoskeleton in transfected cells but is to the I-band in striated muscle. the that muscle-specific proteins to STARS to the STARS also the the potential of proteins in its STARS expression is in cardiac and skeletal muscle during the of when the into the sarcomere M. J. Cell 1999; PubMed Google Scholar, Trends Cell Biol. 2000; 10: Full Text Full Text PDF PubMed Scopus Google Scholar). the of its expression and its actin binding it is tempting to speculate that STARS participate in sarcomere by actin polymerization and cross-linking during striated muscle expression of STARS during Rho signaling, which has been shown to be required for muscle differentiation L. R. A. J. Biol. Chem. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar). Consistent with studies actin dynamics in the control of SRF-dependent transcription (7Sotiropoulos A. Gineitis D. Copeland J. Treisman R. Cell. 1999; 98: 159-169Abstract Full Text Full Text PDF PubMed Scopus (572) Google Scholar, 15Mack C.P. Somlyo A.V. Hautmann M. Somlyo A.P. Owens G.K. J. Biol. Chem. 2001; 276: 341-347Abstract Full Text Full Text PDF PubMed Scopus (324) Google Scholar, L. L. J.A. K. J. 2001; 15: PubMed Scopus Google Scholar), STARS stimulates the activity of The conserved region of STARS is both and for SRF activation and actin the between these that the of STARS SRF are to its the of SRF activity is with muscle as as with an of CArG we that the of STARS are specifically at SRF transcription factor that with is the mechanism for activation of SRF by A of a potential mechanism of of STARS the of the of actin dynamics is shown in Actin the distribution of the monomeric and polymerized studies that the activity of SRF (7Sotiropoulos A. Gineitis D. Copeland J. Treisman R. Cell. 1999; 98: 159-169Abstract Full Text Full Text PDF PubMed Scopus (572) Google Scholar). suggest that STARS activates SRF by this influence a of its to stimulate actin and thereby the a mechanism for the of latrunculin which Cell Biol. 2000; PubMed Scopus Google Scholar), to with the activity of polymerization of actin by STARS to be to SRF of actin polymerization is not to for the of STARS SRF this is STARS is to SRF activity in the of cytochalasin which actin polymerization by binding to the of where it further of actin D also stimulates SRF activity by the of (7Sotiropoulos A. Gineitis D. Copeland J. Treisman R. Cell. 1999; 98: 159-169Abstract Full Text Full Text PDF PubMed Scopus (572) Google Scholar, 15Mack C.P. Somlyo A.V. Hautmann M. Somlyo A.P. Owens G.K. J. Biol. Chem. 2001; 276: 341-347Abstract Full Text Full Text PDF PubMed Scopus (324) Google Scholar). STARS acts through a In SRF it required for SRF activation (7Sotiropoulos A. Gineitis D. Copeland J. Treisman R. Cell. 1999; 98: 159-169Abstract Full Text Full Text PDF PubMed Scopus (572) Google Scholar). In light of the actin binding of it stimulate SRF by as a to is to that has been shown to to the A. M. M. EMBO J. 1998; PubMed Scopus Google Scholar) and also to be contained the A. M. M. EMBO J. 1998; PubMed Scopus Google Scholar, K. O.J. Y. K. A. Crabtree G.R. Cell. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar, O.J. Zhao K. Crabtree G.R. Trends Cell Biol. 2000; 10: 92-97Abstract Full Text Full Text PDF PubMed Scopus (214) Google Scholar). STARS the of actin into this is an SRF activates muscle-specific transcription by transcription factors as and Mol. Biol. Cell. 1996; Google Scholar, M. Mol. Cell. Biol. 2000; PubMed Scopus Google Scholar, S. A. M. Mol. Cell. Biol. 2001; PubMed Scopus Google Scholar, D. L. J.A. Olson E.N. Cell. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar). STARS is a muscle-specific protein, its to stimulate SRF activity in cells that it not these transcription factors for The of STARS expression the of myocyte differentiation provides a mechanism for enhancing SRF activity in muscle cells and the expression of SRF-dependent Rho signaling the formation of and the (7Sotiropoulos A. Gineitis D. Copeland J. Treisman R. Cell. 1999; 98: 159-169Abstract Full Text Full Text PDF PubMed Scopus (572) Google Scholar) that the of Rho SRF are to its the cytoskeleton and are mediated by a in as a of actin of SRF activity by STARS is influenced by Rho signaling, the Rho SRF activation by The of the Rho to SRF activation by STARS also Rho as a effector of the that STARS activity also the of other Rho in the mechanism for STARS Rho as that between and nucleotide exchange factors activate Rho by proteins stimulate Aelst L. D'Souza-Schorey C. Genes Dev. 1997; 11: 2295-2322Crossref PubMed Scopus (2080) Google Scholar). 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Chem. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar). of SRF activity by RhoA not Rho activate SRF in cells in which STARS is not it is that RhoA acts in to STARS and that the of RhoA the cytoskeleton gene expression as a effector for we this is STARS activate SRF in J. and N. in which RhoA not actin Cell. 1995; Full Text PDF PubMed Scopus Google Scholar). STARS expression is in adult cardiac and skeletal muscle and is during of the heart in response to activation as as which is associated with activation S. A. 2001; Scopus Google Scholar). organization is a of cardiac of STARS new in of actin with cardiac as in The of the cytoskeleton and sarcomere has a influence gene expression and of muscle cells. The of STARS to activate Rho signaling through actin association a potential between myocyte and the for muscle gene In light of the role of Rho signaling in hypertrophy R. Komuro I. T. Y. S. T. Yazaki Y. 1999; PubMed Scopus Google Scholar) and the of the in Nature. 2001; Scopus Google Scholar), the potential of STARS in signaling during and of striated muscle cells is an for the We J. for with A. for and and N. for the We are to A. Hall and M. for