Divergent Regulation of the Sarcomere and the Cytoskeleton

The existence of a feedback mechanism regulating the precise amounts of muscle structural proteins, such as actin and the actin-associated protein tropomyosin (Tm), in the sarcomeres of striated muscles is well established. However, the regulation of nonmuscle or cytoskeletal actin and Tms in nonmuscle cell structures has not been elucidated. Unlike the thin filaments of striated muscles, the actin cytoskeleton in nonmuscle cells is intrinsically dynamic. Given the differing requirements for the structural integrity of the actin thin filaments of the sarcomere compared with the requirement for dynamicity of the actin cytoskeleton in nonmuscle cells, we postulated that different regulatory mechanisms govern the expression of sarcomeric versus cytoskeletal Tms, as key regulators of the properties of the actin cytoskeleton. Comprehensive analyses of tissues from transgenic and knock-out mouse lines that overexpress the cytoskeletal Tms, Tm3 and Tm5NM1, and a comparison with sarcomeric Tms provide evidence for this. Moreover, we show that overexpression of a cytoskeletal Tm drives the amount of filamentous actin. The existence of a feedback mechanism regulating the precise amounts of muscle structural proteins, such as actin and the actin-associated protein tropomyosin (Tm), in the sarcomeres of striated muscles is well established. However, the regulation of nonmuscle or cytoskeletal actin and Tms in nonmuscle cell structures has not been elucidated. Unlike the thin filaments of striated muscles, the actin cytoskeleton in nonmuscle cells is intrinsically dynamic. Given the differing requirements for the structural integrity of the actin thin filaments of the sarcomere compared with the requirement for dynamicity of the actin cytoskeleton in nonmuscle cells, we postulated that different regulatory mechanisms govern the expression of sarcomeric versus cytoskeletal Tms, as key regulators of the properties of the actin cytoskeleton. Comprehensive analyses of tissues from transgenic and knock-out mouse lines that overexpress the cytoskeletal Tms, Tm3 and Tm5NM1, and a comparison with sarcomeric Tms provide evidence for this. Moreover, we show that overexpression of a cytoskeletal Tm drives the amount of filamentous actin. Actin microfilaments are present in a variety of cellular structures that are specialized for different functions (1Gunning, P. W., O'Neill, G. M., and Hardeman, E. C. (2007) Physiol. Rev., in pressGoogle Scholar). In muscle cells, actin filaments are arranged into the thin filaments of sarcomeres to provide contractile force. Proper functioning of the sarcomere requires an invariant organization of this structure. A mechanism is in place that maintains strict stoichiometric expression of the components of the sarcomere, such as actin and Tms, 2The abbreviations used are:TmtropomyosinMEFmouse embryo fibroblastNTGnontransgenicESembryonic stemZ-LACZ-line adjacent compartment and thus sarcomeric integrity. In contrast, actin microfilaments in nonmuscle cells are involved in a wide range of cellular architectures and functions, including motility, membrane ruffling, adhesion, cytokinesis, and transport. The diverse activities of the actin microfilaments involved in these cellular processes is made possible due to the dynamic nature of the actin cytoskeleton, where actin filaments undergo rapid assembly and disassembly through monomeric to filamentous actin conversion. tropomyosin mouse embryo fibroblast nontransgenic embryonic stem Z-line adjacent compartment Among the extensive array of proteins that interact directly or indirectly with actin (2Ayscough K.R. Curr. Opin. Cell Biol. 1998; 10: 102-111Crossref PubMed Scopus (152) Google Scholar) and regulate the dynamics and assembly of actin filaments, the Tms play an essential role. Tms stabilize actin filaments by modulating the interaction of actin-binding proteins responsible for the regulation of actin dynamics (3Ishikawa R. Yamashiro S. Matsumura F. J. Biol. Chem. 1989; 264: 7490-7497Abstract Full Text PDF PubMed Google Scholar, 4Bernstein B.W. Bamburg J.R. 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PubMed Scopus Google and in in with and in or for by with with with the and to in and is of used protein of Tm3 or has the expression of cytoskeletal Tm of cellular protein from and and by with and and and of not the expression of cytoskeletal Tms in and of protein from and lines and cells by and with and protein by with the in the expression of in the and and sarcomeric Tm isoforms are in the of protein from from the transgenic and the Tm3 and transgenic lines with and protein by with of cytoskeletal Tms not actin of protein from the and of Tm3 and transgenic by and with the actin that cytoskeletal and muscle actin the of of made and and the of with in expressed to of the to for protein The by and the for of and made of the by the of the and the of the the where from the and compared are expressed as a an from and muscles from and and for as Schevzov G. V. B. M. Lin J.J. Weinberger R. Gunning Hardeman E.C. J. Cell Biol. 2004; PubMed Scopus Google Scholar). In muscles fixed in for and to for a with an in to and in in and for and with of for the with for as G. B. N.S. S. M. Gunning J. PubMed Scopus Google Scholar). in the as for that cells fixed in and with for of Tms a the that cytoskeletal Tm isoforms are not to feedback we transgenic mouse that overexpress different cytoskeletal Tm isoforms by different Tm Tm3 is a by the and is expressed in the of is a by the and is expressed G. B. N.S. S. M. Gunning J. PubMed Scopus Google Scholar, G. N.S. R. J. Lin J.J. Hardeman E. Weinberger R. Gunning P. Mol. Biol. Cell. PubMed Google Scholar). that of Tm3 and are in transgenic tissues of the mouse and is not possible to the Tm3 from a used to the of the established that the are expressed in a range of we a of the of expression cytoskeletal Tm three that the Tm isoforms from the Tm genes G. B. N.S. S. M. Gunning J. PubMed Scopus Google Scholar). tissues from Tm3 transgenic and that in the of cytoskeletal Tm proteins and A and in expression of the Tm or or Tm isoforms by the in the of expression of or in transgenic tissues and The amount of cytoskeletal isoforms in the transgenic with the is due to the expressed and and in the and the expression in these tissues established In Tm3 and proteins in tissues are that cytoskeletal protein not to In in expression of isoforms are the cytoskeletal Tm is not used in this is a of Tm used in this the isoforms and the Tm from are The Tm genes and are to as and (13Perry S.V. J. Muscle Res. Cell Motil. 2001; 22: 5-49Crossref PubMed Scopus (401) Google and G. Gunning P. Jeffrey P.L. C. Helfman D.M. Lin J.J. Weinberger R.P. Mol. Cell 1997; PubMed Scopus Google and J.M. Schevzov G. K. B. J.L. Gunning Mol. Biol. Cell. 2004; PubMed Scopus Google from the J.R. Lin J.J. Cell Motil. PubMed Scopus Google Gunning P. Jeffrey P.L. Weinberger R.P. Mol. 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Boivin G.P. Neumann J. Wieczorek D.F. J. Biol. Chem. 1995; 270: 30593-30603Abstract Full Text Full Text PDF PubMed Scopus (127) Google Scholar). overexpression of in the to a in the expression of M. Grupp I.L. Grupp G. O'Toole B.A. Kier A.B. Boivin G.P. Neumann J. Wieczorek D.F. J. Biol. Chem. 1995; 270: 30593-30603Abstract Full Text Full Text PDF PubMed Scopus (127) Google Scholar) the expression of cytoskeletal Tm isoforms and In to that cytoskeletal Tms are with muscle in cells the we the of a cytoskeletal by in the by and is present in filaments that the of the cells A of has been in muscle S. J. A. K. P. W., and Hardeman, E. C. Cell Motil. in pressGoogle Scholar). we that in expression of the mouse Tm the transgenic overexpression of Tm3 or these that the regulation of the cytoskeletal Tms is the in or nonmuscle and is from the mechanism regulating sarcomeric Tm Tm to the as the Tm that the of cytoskeletal Tm for the of actin the is that cytoskeletal Tm protein in the transgenic tissues into the structures as in the of in and and in muscle from the transgenic mouse we the transgenic protein expression a and are present in the the of the cell A and and to a the A and of expressed to the compartment the sarcomere as the and of muscle with or and show that and to the Z-line adjacent compartment Schevzov G. V. B. M. Lin J.J. Weinberger R. Gunning Hardeman E.C. J. Cell Biol. 2004; PubMed Scopus Google Scholar). Actin of Tm3 and the that actin expression overexpression of Tm3 or actin that nonmuscle and muscle actin J.L. Cell Motil. 10: PubMed Scopus Google Scholar) used to actin and we found that the of actin in transgenic tissues A and and Moreover, in the of or in transgenic tissues not is in with the that overexpression of the cytoskeletal isoforms and in a cell not expression of actin N.S. Schevzov G. Ferguson V. Percival J.M. Lin J.J. Matsumura F. Bamburg J.R. Jeffrey P.L. Hardeman E.C. Gunning P. Weinberger R.P. Mol. Biol. Cell. 2003; 14: 1002-1016Crossref PubMed Scopus (193) Google Scholar). overexpression of cytoskeletal Tm isoforms not the expression of actin or cytoskeletal Tm of the has been as a actin-binding protein (13Perry S.V. J. Muscle Res. Cell Motil. 2001; 22: 5-49Crossref PubMed Scopus (401) Google Scholar). actin protein Tm is possible that Tm an in the of actin have this in from transgenic from the an of the expressed with the in The from are of in the with an in in the is to that in the from the the is that cytoskeletal Tm actin In this we that the Tms are to a different regulatory mechanism the sarcomere-associated this is for the cytoskeletal Tms present in muscle and nonmuscle the regulation of the of Tm isoforms is to to the sarcomere and the cytoskeleton. that the of a feedback mechanism to regulate cytoskeletal Tm expression the of expression to a dynamic and actin cytoskeleton. overexpression of cytoskeletal Tm3 or in different mouse tissues the expression of cytoskeletal Tm In an in a M. Helfman D.M. S. A. 1996; PubMed Scopus Google Scholar). is in to that have been made for contractile of M. Grupp I.L. Grupp G. O'Toole B.A. Kier A.B. Boivin G.P. Neumann J. Wieczorek D.F. J. Biol. Chem. 1995; 270: 30593-30603Abstract Full Text Full Text PDF PubMed Scopus (127) Google a of (14Palermo J. Gulick J. Colbert M. Fewell J. Robbins J. Circ. Res. 1996; 78: 504-509Crossref PubMed Scopus (117) Google J. Hewett T.E. Klevitsky R. Buck S.H. Moss R.L. Robbins J. Circ. Res. 1997; 80: 655-664Crossref PubMed Scopus (80) Google essential J.G. Hewett T.E. Sanbe A. Klevitsky R. Hayes E. Warshaw D. Maughan D. Robbins J. J. Clin. Invest. 1998; 101: 2630-2639Crossref PubMed Scopus (75) Google actin A. Crawford K. Flick R. Klevitsky R. Lorenz J.N. Bove K.E. Robbins J. Lessard J.L. Transgenic Res. 2004; 13: 531-540Crossref PubMed Scopus (15) Google and an in muscle M.A. P.A. A. Gunning Hardeman E.C. PubMed Scopus Google Scholar) in transgenic the of a Moreover, of protein associated with M. Pieples K. Rethinasamy P. Hoit B. Grupp I.L. Boivin G.P. Wolska B. Evans C. Solaro R.J. Wieczorek D.F. Circ. Res. 1999; 85: 47-56Crossref PubMed Scopus (128) Google Scholar, 20Prabhakar R. Boivin G.P. Grupp I.L. Hoit B. Arteaga G. Solaro J.R. Wieczorek D.F. J. Mol. Cell Cardiol. 2001; 33: 1815-1828Abstract Full Text PDF PubMed Scopus (103) Google Scholar) are knock-out of A. Crawford K. L. M. Lorenz J. S. J. Neumann J. Robbins J. Boivin G.P. O'Toole B.A. Lessard J.L. S. A. 1997; PubMed Scopus Google K. Flick R. L. D. R. Bove K. A. Lessard J. Mol. Cell. Biol. 2002; 22: PubMed Scopus Google or muscle actin R. G. M. A. R.J. J. 14: PubMed Scopus Google Scholar) with an in the expression of an actin the of contractile proteins is in by feedback mechanisms that to the protein to a strict is The of sarcomeric Tms is regulation of muscle In contrast, is a of cytoskeletal Tm The cytoskeletal Tm isoforms have been in R.J. Lin J.J. J. Cell 1996; Google the J.M. Schevzov G. K. B. J.L. Gunning Mol. Biol. Cell. 2004; PubMed Scopus Google Scholar, K. Percival J.M. Weinberger R. Gunning P. J.L. J. Biol. Chem. 1999; 274: Full Text Full Text PDF PubMed Scopus Google cellular G. Helfman D.M. Curr. Opin. 2001; 11: PubMed Scopus Google and Schevzov G. Gunning P. Weinberger R.P. 2003; PubMed Scopus Google and regulate the organization of actin filaments N.S. Schevzov G. Ferguson V. Percival J.M. Lin J.J. Matsumura F. Bamburg J.R. Jeffrey P.L. Hardeman E.C. Gunning P. Weinberger R.P. Mol. Biol. Cell. 2003; 14: 1002-1016Crossref PubMed Scopus (193) Google Scholar). of these functions is we that the of a feedback mechanism to a of cytoskeletal filaments for the regulation of actin filaments with In this we that expressed in embryonic is into the compartment into the the of the that the expressed to the the muscle as the In we that is in to the of and results in of embryonic G. N.S. R. J. Lin J.J. Hardeman E. Weinberger R. Gunning P. Mol. Biol. Cell. PubMed Google Scholar). is that the cytoskeleton of cytoskeletal Tm expression in are the cytoskeletal and sarcomeric Tm isoforms to to a Schevzov G. Hardeman E.C. Cell Biol. Full Text Full Text PDF PubMed Scopus Google Scholar). is in muscle where sarcomeric Tms to the actin thin filaments of the sarcomere, and cytoskeletal Tms to cytoskeletal filaments in the that is from the sarcomere Schevzov G. V. B. M. Lin J.J. Weinberger R. Gunning Hardeman E.C. J. Cell Biol. 2004; PubMed Scopus Google Scholar). is transgenic expressed exclusively to the thin filaments of the sarcomere M.A. P.A. A. Gunning Hardeman E.C. PubMed Scopus Google whereas expressed cytoskeletal Tm3 exclusively to the Schevzov G. V. B. M. Lin J.J. Weinberger R. Gunning Hardeman E.C. J. Cell Biol. 2004; PubMed Scopus Google Scholar). The of Tm3 in muscle to cytoskeletal filaments is given that this is a muscle Tms and and is not expressed in muscle the existence of a mechanism to regulate the of sarcomeric versus cytoskeletal the of isoforms to into the thin filaments the sarcomeres and to M.A. P.A. A. Gunning Hardeman E.C. PubMed Scopus Google whereas expressed Tm3 to the and a Schevzov G. V. B. M. Lin J.J. Weinberger R. Gunning Hardeman E.C. J. Cell Biol. 2004; PubMed Scopus Google Scholar). A possible for such is to properties to microfilaments and to regulate these of actin The of is in the are with the that a feedback regulatory mechanism the protein of sarcomeric a mechanism that precise protein is the structural proteins in the In the of the knock-out mouse P. M. Hewett Boivin G. Wolska Evans C. Solaro R.J. Wieczorek D.F. Circ. Res. 1998; PubMed Scopus Google translational is to play a in regulating Tm whereas transgenic overexpression regulation the and translational M. Grupp I.L. Grupp G. O'Toole B.A. Kier A.B. Boivin G.P. Neumann J. Wieczorek D.F. J. Biol. Chem. 1995; 270: 30593-30603Abstract Full Text Full Text PDF PubMed Scopus (127) Google Scholar). In this we that the of cytoskeletal filaments is not cytoskeletal Tm not to the of Tm to the cytoskeletal Tm feedback regulation that to an in the of an in the we a drives the of to in the of filament that to of of in the of with Actin filaments Tm have been found in and the of cells L. C. C. J. J. A. J. Cell Google Scholar, G. Gunning P. Jeffrey P.L. C. Helfman D.M. Lin J.J. Weinberger R.P. Mol. Cell 1997; PubMed Scopus Google Scholar, V. J. Hitchcock-DeGregori S.E. J. Cell 2002; PubMed Scopus Google Scholar). In contrast, the striated muscle thin filament is with muscle Tm and the of the filaments is by the of the the for muscle Tm is to the muscle Tm to this is the that Tms not are found in with actin. expression of sarcomeric Tms in M. Grupp I.L. Grupp G. O'Toole B.A. Kier A.B. Boivin G.P. Neumann J. Wieczorek D.F. J. Biol. Chem. 1995; 270: 30593-30603Abstract Full Text Full Text PDF PubMed Scopus (127) Google Scholar, 19Muthuchamy M. Pieples K. Rethinasamy P. Hoit B. Grupp I.L. 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