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• W3136692316 abstract "Myocardin-related transcription factor A (MRTFA) is a coactivator of serum response factor, a transcription factor that participates in several critical cellular functions including cell growth and apoptosis. MRTFA couples transcriptional regulation to actin cytoskeleton dynamics, and the transcriptional targets of the MRTFA–serum response factor complex include genes encoding cytoskeletal proteins as well as immediate early genes. Previous work has shown that MRTFA promotes the differentiation of many cell types, including various types of muscle cells and hematopoietic cells, and MRTFA's interactions with other protein partners broaden its cellular roles. However, despite being first identified as part of the recurrent t(1;22) chromosomal translocation in acute megakaryoblastic leukemia, the mechanisms by which MRTFA functions in malignant hematopoiesis have yet to be defined. In this review, we provide an in-depth examination of the structure, regulation, and known functions of MRTFA with a focus on hematopoiesis. We conclude by identifying areas of study that merit further investigation. Myocardin-related transcription factor A (MRTFA) is a coactivator of serum response factor, a transcription factor that participates in several critical cellular functions including cell growth and apoptosis. MRTFA couples transcriptional regulation to actin cytoskeleton dynamics, and the transcriptional targets of the MRTFA–serum response factor complex include genes encoding cytoskeletal proteins as well as immediate early genes. Previous work has shown that MRTFA promotes the differentiation of many cell types, including various types of muscle cells and hematopoietic cells, and MRTFA's interactions with other protein partners broaden its cellular roles. However, despite being first identified as part of the recurrent t(1;22) chromosomal translocation in acute megakaryoblastic leukemia, the mechanisms by which MRTFA functions in malignant hematopoiesis have yet to be defined. In this review, we provide an in-depth examination of the structure, regulation, and known functions of MRTFA with a focus on hematopoiesis. We conclude by identifying areas of study that merit further investigation. Myocardin-related transcription factor A (MRTFA), which has also been named MKL1, MAL, or BSAC, is expressed in most cells. First identified as a member of the fusion product resulting from the recurrent t(1;22)(p13;q13) chromosomal translocation found uniquely in pediatric acute megakaryoblastic leukemia (AMKL), its primary function lies in its ability to coactivate the transcription factor serum response factor (SRF) and thereby induce the transcription of genes affecting cell migration, adhesion, and structure (1Ma Z. Morris S.W. Valentine V. Li M. Herbrick J.A. Cui X. Bouman D. Li Y. Mehta P.K. Nizetic D. Kaneko Y. Chan G.C. Chan L.C. Squire J. Scherer S.W. et al.Fusion of two novel genes, RBM15 and MKL1, in the t(1;22)(p13;q13) of acute megakaryoblastic leukemia.Nat. Genet. 2001; 28: 220-221Crossref PubMed Scopus (244) Google Scholar, 2Mercher T. Coniat M.B. Monni R. Mauchauffe M. Nguyen Khac F. Gressin L. Mugneret F. Leblanc T. Dastugue N. Berger R. Bernard O.A. Involvement of a human gene related to the Drosophila spen gene in the recurrent t(1;22) translocation of acute megakaryocytic leukemia.Proc. Natl. Acad. Sci. U. S. A. 2001; 98: 5776-5779Crossref PubMed Scopus (196) Google Scholar). Through binding to SRF, MRTFA serves as a key regulator not just of hematopoietic differentiation but also muscle and myofibroblast maturation and solid cancer metastasis (3Du K.L. Chen M. Li J. Lepore J.J. Mericko P. Parmacek M.S. Megakaryoblastic leukemia factor-1 transduces cytoskeletal signals and induces smooth muscle cell differentiation from undifferentiated embryonic stem cells.J. Biol. Chem. 2004; 279: 17578-17586Abstract Full Text Full Text PDF PubMed Scopus (135) Google Scholar, 4Smith E.C. Thon J.N. Devine M.T. Lin S. Schulz V.P. Guo Y. Massaro S.A. Halene S. Gallagher P. Italiano Jr., J.E. Krause D.S. MKL1 and MKL2 play redundant and crucial roles in megakaryocyte maturation and platelet formation.Blood. 2012; 120: 2317-2329Crossref PubMed Scopus (48) Google Scholar, 5Gilles L. Bluteau D. Boukour S. Chang Y. Zhang Y. Robert T. Dessen P. Debili N. Bernard O.A. Vainchenker W. Raslova H. MAL/SRF complex is involved in platelet formation and megakaryocyte migration by regulating MYL9 (MLC2) and MMP9.Blood. 2009; 114: 4221-4232Crossref PubMed Scopus (62) Google Scholar, 6Cen B. Selvaraj A. Burgess R.C. Hitzler J.K. Ma Z. Morris S.W. Prywes R. Megakaryoblastic leukemia 1, a potent transcriptional coactivator for serum response factor (SRF), is required for serum induction of SRF target genes.Mol. Cell Biol. 2003; 23: 6597-6608Crossref PubMed Scopus (248) Google Scholar, 7Cen B. Selvaraj A. Prywes R. Myocardin/MKL family of SRF coactivators: Key regulators of immediate early and muscle specific gene expression.J. Cell Biochem. 2004; 93: 74-82Crossref PubMed Scopus (135) Google Scholar). This wide range of functions in both normal and pathological processes, as well as in multiple tissue types, makes MRTFA a worthy candidate for further research and investigation. Roles for the other two members of the myocardin-related transcription factor family (myocardin and MRTFB, alias MKL2) in both cytoskeletal reorganization and cell differentiation have been described (7Cen B. Selvaraj A. Prywes R. Myocardin/MKL family of SRF coactivators: Key regulators of immediate early and muscle specific gene expression.J. Cell Biochem. 2004; 93: 74-82Crossref PubMed Scopus (135) Google Scholar). Myocardin's role is best characterized for cardiac and smooth muscle cells, where it is predominantly expressed. MRTFB is more widely expressed than myocardin and is also critical for cardiac muscle and blood vessel development; Mrtfb knockout (KO) in mice is embryonic lethal because of defective cardiovascular development (8Wei K. Che N. Chen F. Myocardin-related transcription factor B is required for normal mouse vascular development and smooth muscle gene expression.Dev. Dyn. 2007; 236: 416-425Crossref PubMed Scopus (17) Google Scholar, 9Li J. Zhu X. Chen M. Cheng L. Zhou D. Lu M.M. Du K. Epstein J.A. Parmacek M.S. Myocardin-related transcription factor B is required in cardiac neural crest for smooth muscle differentiation and cardiovascular development.Proc. Natl. Acad. Sci. U. S. A. 2005; 102: 8916-8921Crossref PubMed Scopus (121) Google Scholar, 10Oh J. Richardson J.A. Olson E.N. Requirement of myocardin-related transcription factor-B for remodeling of branchial arch arteries and smooth muscle differentiation.Proc. Natl. Acad. Sci. U. S. A. 2005; 102: 15122-15127Crossref PubMed Scopus (125) Google Scholar). In the adult, MRTFB has not been widely studied, with most reported functions of MRTFB largely redundant with those of MRTFA. In contrast, MRTFA has been widely studied in the adult (4Smith E.C. Thon J.N. Devine M.T. Lin S. Schulz V.P. Guo Y. Massaro S.A. Halene S. Gallagher P. Italiano Jr., J.E. Krause D.S. MKL1 and MKL2 play redundant and crucial roles in megakaryocyte maturation and platelet formation.Blood. 2012; 120: 2317-2329Crossref PubMed Scopus (48) Google Scholar, 7Cen B. Selvaraj A. Prywes R. Myocardin/MKL family of SRF coactivators: Key regulators of immediate early and muscle specific gene expression.J. Cell Biochem. 2004; 93: 74-82Crossref PubMed Scopus (135) Google Scholar). Here, we focus on MRTFA and its critical role in hematopoiesis. In addition to its primary role as a transcriptional coactivator for SRF, MRTFA also interacts with other proteins (e.g., SMADs) in an SRF-independent manner. While interactions between MRTFA and proteins other than SRF have been observed, the relative impact of these interactions on cellular and cytoskeletal function is not yet clear. This promising area of research may shed more light on the role of MRTFA in hematopoietic cell differentiation and AMKL. The significance of a better understanding of MRTFA is multifold. In addition to a role in AMKL, MRTFA has been clearly implicated in normal hematopoiesis, immune function, wound healing, and cancer metastasis (10Oh J. Richardson J.A. Olson E.N. Requirement of myocardin-related transcription factor-B for remodeling of branchial arch arteries and smooth muscle differentiation.Proc. Natl. Acad. Sci. U. S. A. 2005; 102: 15122-15127Crossref PubMed Scopus (125) Google Scholar, 11Selvaraj A. Prywes R. Megakaryoblastic leukemia-1/2, a transcriptional co-activator of serum response factor, is required for skeletal myogenic differentiation.J. Biol. Chem. 2003; 278: 41977-41987Abstract Full Text Full Text PDF PubMed Scopus (114) Google Scholar). Elucidating the mechanisms by which MRTFA drives normal differentiation in the many cell types in which it is expressed could lead to the identification of novel therapeutics not only for AMKL but other diseases as well. In this review, we aim to provide a comprehensive overview of the current state of research surrounding MRTFA, with a focus on what is known about its role in hematopoietic cells, and conclude with areas that are worthy of further exploration. Figure 1 shows the exon organization and subsequent protein isoforms encoded by the different transcriptional start site and splice variants of MRTFA. MRTFA has five principal functional protein domains and is encoded by 15 exons. The N terminus of the protein contains a number of RPEL motifs. Canonical RPEL motifs have the amino acid sequence RPxxxEL, where x can be any amino acid. The first RPEL-like sequence of MRTFA, referred to as RPEL1 and encoded by exon 4, has the sequence RRxxxEL and is thus not a “true” RPEL motif. RPEL2 and RPEL3 are canonical and are encoded by exons 6 and 7. These RPEL domains are required for the interaction between MRTFA and monomeric G-actin that regulates the cellular localization and activity of MRTFA. Highly disordered in the unbound protein, RPEL2 and RPEL3 are induced to form stable alpha helices upon binding to G-actin (12Mizuguchi M. Fuju T. Obita T. Ishikawa M. Tsuda M. Tabuchi A. Transient alpha-helices in the disordered RPEL motifs of the serum response factor coactivator MKL1.Sci. Rep. 2014; 4: 5224Crossref PubMed Scopus (9) Google Scholar). Deletion of the RPEL domains renders the protein predominantly nuclear and constitutively active (13Miralles F. Posern G. Zaromytidou A.I. Treisman R. Actin dynamics control SRF activity by regulation of its coactivator MAL.Cell. 2003; 113: 329-342Abstract Full Text Full Text PDF PubMed Scopus (1051) Google Scholar). While one transcript variant of MRTFA contains only RPEL2 and RPEL3, the others also contain the noncanonical RPEL1 (Fig. 1) (6Cen B. Selvaraj A. Burgess R.C. Hitzler J.K. Ma Z. Morris S.W. Prywes R. Megakaryoblastic leukemia 1, a potent transcriptional coactivator for serum response factor (SRF), is required for serum induction of SRF target genes.Mol. Cell Biol. 2003; 23: 6597-6608Crossref PubMed Scopus (248) Google Scholar, 13Miralles F. Posern G. Zaromytidou A.I. Treisman R. Actin dynamics control SRF activity by regulation of its coactivator MAL.Cell. 2003; 113: 329-342Abstract Full Text Full Text PDF PubMed Scopus (1051) Google Scholar). Although the significance of these transcript variants is not yet clear, Guettler et al. showed that in transcript variants containing three RPEL motifs, RPEL2 and RPEL3 are most critical for actin binding with RPEL1 playing a lesser role (14Guettler S. Vartiainen M.K. Miralles F. Larijani B. Treisman R. RPEL motifs link the serum response factor cofactor MAL but not myocardin to Rho signaling via actin binding.Mol. Cell Biol. 2008; 28: 732-742Crossref PubMed Scopus (124) Google Scholar). MRTFA contains two regions enriched for basic residues (e.g., lysine and arginine), located on either side of RPEL3. The first basic domain, encoded by exon 7 upstream of RPEL3, contains a nuclear localization signal, and promotes MRTFA nuclear localization (6Cen B. Selvaraj A. Burgess R.C. Hitzler J.K. Ma Z. Morris S.W. Prywes R. Megakaryoblastic leukemia 1, a potent transcriptional coactivator for serum response factor (SRF), is required for serum induction of SRF target genes.Mol. Cell Biol. 2003; 23: 6597-6608Crossref PubMed Scopus (248) Google Scholar, 13Miralles F. Posern G. Zaromytidou A.I. Treisman R. Actin dynamics control SRF activity by regulation of its coactivator MAL.Cell. 2003; 113: 329-342Abstract Full Text Full Text PDF PubMed Scopus (1051) Google Scholar). The second basic domain, encoded within exon 10, also plays a role in nuclear localization, but its primary function is to bind SRF. SRF binding occurs via an interaction between a hydrophobic β-sheet in MRTFA and a hydrophobic pocket in the DNA-binding domain of SRF (6Cen B. Selvaraj A. Burgess R.C. Hitzler J.K. Ma Z. Morris S.W. Prywes R. Megakaryoblastic leukemia 1, a potent transcriptional coactivator for serum response factor (SRF), is required for serum induction of SRF target genes.Mol. Cell Biol. 2003; 23: 6597-6608Crossref PubMed Scopus (248) Google Scholar, 14Guettler S. Vartiainen M.K. Miralles F. Larijani B. Treisman R. RPEL motifs link the serum response factor cofactor MAL but not myocardin to Rho signaling via actin binding.Mol. Cell Biol. 2008; 28: 732-742Crossref PubMed Scopus (124) Google Scholar). The second basic domain is critical for most known functions of MRTFA. Deletion of the two basic regions prevents MRTFA from accumulating in the nucleus (6Cen B. Selvaraj A. Burgess R.C. Hitzler J.K. Ma Z. Morris S.W. Prywes R. Megakaryoblastic leukemia 1, a potent transcriptional coactivator for serum response factor (SRF), is required for serum induction of SRF target genes.Mol. Cell Biol. 2003; 23: 6597-6608Crossref PubMed Scopus (248) Google Scholar). Downstream of the basic domains is a glutamine-rich region canonically referred to as the “Q-rich” domain. Though no function for the Q-rich domain of MRTFA has been identified, the Q-rich domain of the related protein myocardin binds SRF (13Miralles F. Posern G. Zaromytidou A.I. Treisman R. Actin dynamics control SRF activity by regulation of its coactivator MAL.Cell. 2003; 113: 329-342Abstract Full Text Full Text PDF PubMed Scopus (1051) Google Scholar, 15Sprenkeler E.G.G. Henriet S. Tool A. Kreft I.C. van der Bijl I. Aarts C. van Houdt M. Verkuijlen P. van Aerde K. Jaspers G. van Heijst A. Koole W. Gardeitchik T. Geissler J. de Boer M. et al.MKL1 deficiency results in a severe neutrophil motility defect due to impaired actin polymerization.Blood. 2020; 135: 2171-2181Crossref PubMed Scopus (23) Google Scholar, 16Wang D.Z. Li S. Hockemeyer D. Sutherland L. Wang Z. Schratt G. Richardson J.A. Nordheim A. Olson E.N. Potentiation of serum response factor activity by a family of myocardin-related transcription factors.Proc. Natl. Acad. Sci. U. S. A. 2002; 99: 14855-14860Crossref PubMed Scopus (404) Google Scholar). Of potential interest is the SAP domain, named for the SAF-A/B, Acinus, and PIAS proteins in which it was discovered and which mediates binding to DNA in those three proteins. SAP domains form amphipathic helices, which are required for this DNA-binding ability (17Aravind L. Koonin E.V. Sap - a putative DNA-binding motif involved in chromosomal organization.Trends Biochem. Sci. 2000; 25: 112-114Abstract Full Text Full Text PDF PubMed Scopus (412) Google Scholar). DNA binding via the SAP domain has not been convincingly demonstrated for MRTFA. The coding sequence of the SAP domain starts at the 3′ end of exon 11 and continues into exon 12. Deletion of the SAP domain has no effect on the ability of MRTFA to activate SRF-mediated transcription in transient transfection assays in HeLa cells (6Cen B. Selvaraj A. Burgess R.C. Hitzler J.K. Ma Z. Morris S.W. Prywes R. Megakaryoblastic leukemia 1, a potent transcriptional coactivator for serum response factor (SRF), is required for serum induction of SRF target genes.Mol. Cell Biol. 2003; 23: 6597-6608Crossref PubMed Scopus (248) Google Scholar). However, it has been suggested that the SAP domain may be required for MRTFA to activate transcription independent of SRF (18Asparuhova M.B. Ferralli J. Chiquet M. Chiquet-Ehrismann R. The transcriptional regulator megakaryoblastic leukemia-1 mediates serum response factor-independent activation of tenascin-C transcription by mechanical stress.FASEB J. 2011; 25: 3477-3488Crossref PubMed Scopus (45) Google Scholar, 19Gurbuz I. Ferralli J. Roloff T. Chiquet-Ehrismann R. Asparuhova M.B. SAP domain-dependent Mkl1 signaling stimulates proliferation and cell migration by induction of a distinct gene set indicative of poor prognosis in breast cancer patients.Mol. Cancer. 2014; 13: 22Crossref PubMed Scopus (37) Google Scholar). Following the SAP domain, also encoded by exon 12, is a conserved leucine-zipper (LZ) domain. Found in many proteins, including others of the myocardin family, the LZ domain enables MRTFA homodimerizeration as well as heterodimerization with MRTFB or myocardin (3Du K.L. Chen M. Li J. Lepore J.J. Mericko P. Parmacek M.S. Megakaryoblastic leukemia factor-1 transduces cytoskeletal signals and induces smooth muscle cell differentiation from undifferentiated embryonic stem cells.J. Biol. Chem. 2004; 279: 17578-17586Abstract Full Text Full Text PDF PubMed Scopus (135) Google Scholar, 11Selvaraj A. Prywes R. Megakaryoblastic leukemia-1/2, a transcriptional co-activator of serum response factor, is required for skeletal myogenic differentiation.J. Biol. Chem. 2003; 278: 41977-41987Abstract Full Text Full Text PDF PubMed Scopus (114) Google Scholar). Deletion of the LZ domain decreases, but does not abolish, activation of SRF target genes, indicating that MRTFA preferentially binds SRF as a dimer, but this is not obligatory (11Selvaraj A. Prywes R. Megakaryoblastic leukemia-1/2, a transcriptional co-activator of serum response factor, is required for skeletal myogenic differentiation.J. Biol. Chem. 2003; 278: 41977-41987Abstract Full Text Full Text PDF PubMed Scopus (114) Google Scholar). At the C terminus of MRTFA is a transcriptional activation domain (TAD), beginning in exon 12 and continuing through exon 15. Deletion of this domain, from amino acid residue 630 onward, prevents the activation of MRTFA target genes and acts as a dominant negative form of MRTFA (6Cen B. Selvaraj A. Burgess R.C. Hitzler J.K. Ma Z. Morris S.W. Prywes R. Megakaryoblastic leukemia 1, a potent transcriptional coactivator for serum response factor (SRF), is required for serum induction of SRF target genes.Mol. Cell Biol. 2003; 23: 6597-6608Crossref PubMed Scopus (248) Google Scholar). Record et al. described a patient with a homozygous nonsense mutation in this domain that resulted in decreased transcription of actin in neutrophils, deleteriously affecting the process of phagocytosis and inducing severe immunodeficiency (20Record J. Malinova D. Zenner H.L. Plagnol V. Nowak K. Syed F. Bouma G. Curtis J. Gilmour K. Cale C. Hackett S. Charras G. Moulding D. Nejentsev S. Thrasher A.J. et al.Immunodeficiency and severe susceptibility to bacterial infection associated with a loss-of-function homozygous mutation of MKL1.Blood. 2015; 126: 1527-1535Crossref PubMed Scopus (52) Google Scholar). Some or all of the five domains described above (RPEL, basic, SAP, LZ, and TAD) are present in all reported isoforms of MRTFA. To date, five mRNA transcript variants (TVs) of human MRTFA (hMRTFA) have been reported, each containing between 12 and 15 exons. In all forms of the protein, exons 1 and 2 are not translated. Translation of hMRTFA-TV1 (referred to as MKL1_L by Scharenberg et al.), hMRTFA-TV3, and hMRTFA-TV4 are initiated by a nontraditional GTG start codon in exon 3 (21Scharenberg M.A. Pippenger E.B. Sack R. Zingg D. Ferralli J. Schenk S. Martin I. Chiquet-Ehrismann R. TGF-beta-induced differentiation into myofibroblasts involves specific regulation of two MKL1 isoforms.J. Cell Sci. 2014; 127: 1079-1091Crossref PubMed Scopus (72) Google Scholar). Kozak et al. define a flanking consensus sequence required for GTG to function as a start codon, which is present in exon 3; an alternative tRNA is utilized in this context, which translates the alternative start codon as methionine (22Kozak M. Context effects and inefficient initiation at non-AUG codons in eucaryotic cell-free translation systems.Mol. Cell Biol. 1989; 9: 5073-5080Crossref PubMed Scopus (374) Google Scholar). As hMRTFA-TV1, hMRTFA-TV3, and hMRTFA-TV4 each contain a complete exon 4, which encodes RPEL1, each of these isoforms contain all three RPEL domains. TVs hMRTFA-TV1 and hMRTFA-TV3 have alternative splicing and/or stop codons as depicted in Figure 1. The translated protein encoded by hMRTFA-TV2, which begins with a traditional ATG in exon 4, is the only isoform to lack RPEL1. hMRTFA-TV5 (referred to as MKL1_S by Scharenberg et al.) begins with an alternate exon 3, termed exon 3′, but proceeds to canonical exon 4, resulting in a translated protein with three RPEL motifs (21Scharenberg M.A. Pippenger E.B. Sack R. Zingg D. Ferralli J. Schenk S. Martin I. Chiquet-Ehrismann R. TGF-beta-induced differentiation into myofibroblasts involves specific regulation of two MKL1 isoforms.J. Cell Sci. 2014; 127: 1079-1091Crossref PubMed Scopus (72) Google Scholar). The differential expression of these TVs and their relative significance to the function of MRTFA remains unclear. Scharenberg et al. confirm expression of at least hMRTFA-TV1, hMRTFA-TV2, and hMRTFA-TV5 in human tissues and also indicate that each of these TVs can activate SRF; however, thus far, only hMRTFA-TV1 and hMRTFA-TV2 have been found to be expressed in mice (13Miralles F. Posern G. Zaromytidou A.I. Treisman R. Actin dynamics control SRF activity by regulation of its coactivator MAL.Cell. 2003; 113: 329-342Abstract Full Text Full Text PDF PubMed Scopus (1051) Google Scholar, 21Scharenberg M.A. Pippenger E.B. Sack R. Zingg D. Ferralli J. Schenk S. Martin I. Chiquet-Ehrismann R. TGF-beta-induced differentiation into myofibroblasts involves specific regulation of two MKL1 isoforms.J. Cell Sci. 2014; 127: 1079-1091Crossref PubMed Scopus (72) Google Scholar). Scharenberg et al. also postulate that exon 3′, the start site of hMRTFA-TV5, is linked to a different promoter (21Scharenberg M.A. Pippenger E.B. Sack R. Zingg D. Ferralli J. Schenk S. Martin I. Chiquet-Ehrismann R. TGF-beta-induced differentiation into myofibroblasts involves specific regulation of two MKL1 isoforms.J. Cell Sci. 2014; 127: 1079-1091Crossref PubMed Scopus (72) Google Scholar). Ishikawa et al. propose that because of the missing RPEL1 in hMRTFA-TV2, this isoform of MRTFA may have decreased affinity for actin and thus increased nuclear localization, but this is disputed by the assessment by Guettler et al. that RPEL1 does not play a significant role in actin binding (14Guettler S. Vartiainen M.K. Miralles F. Larijani B. Treisman R. RPEL motifs link the serum response factor cofactor MAL but not myocardin to Rho signaling via actin binding.Mol. Cell Biol. 2008; 28: 732-742Crossref PubMed Scopus (124) Google Scholar, 23Ishikawa M. Shiota J. Ishibashi Y. Hakamata T. Shoji S. Fukuchi M. Tsuda M. Shirao T. Sekino Y. Ohtsuka T. Baraban J.M. Tabuchi A. Identification, expression and characterization of rat isoforms of the serum response factor (SRF) coactivator MKL1.FEBS Open Bio. 2013; 3: 387-393Crossref PubMed Scopus (12) Google Scholar). Further investigation into functions of each of these TVs in discrete cell types and developmental stages is critical to elucidating the role of MRTFA in cell maturation and leukemogenesis. Overall, the three myocardin family proteins (Fig. 2) have an average of 35% similarity, with increased homology in the five conserved domains (6Cen B. Selvaraj A. Burgess R.C. Hitzler J.K. Ma Z. Morris S.W. Prywes R. Megakaryoblastic leukemia 1, a potent transcriptional coactivator for serum response factor (SRF), is required for serum induction of SRF target genes.Mol. Cell Biol. 2003; 23: 6597-6608Crossref PubMed Scopus (248) Google Scholar, 7Cen B. Selvaraj A. Prywes R. Myocardin/MKL family of SRF coactivators: Key regulators of immediate early and muscle specific gene expression.J. Cell Biochem. 2004; 93: 74-82Crossref PubMed Scopus (135) Google Scholar). Although myocardin contains three RPEL-like motifs, only RPEL3 has a canonical RPEL sequence. The lack of the canonical consensus sequence in the first 2 RPEL-like domains (RPEL1 and RPEL2) in myocardin likely underlies myocardin's low affinity for G-actin and constitutively nuclear localization (14Guettler S. Vartiainen M.K. Miralles F. Larijani B. Treisman R. RPEL motifs link the serum response factor cofactor MAL but not myocardin to Rho signaling via actin binding.Mol. Cell Biol. 2008; 28: 732-742Crossref PubMed Scopus (124) Google Scholar). The RPEL1-like sequences of both MRTFA and MRTFB, while highly similar, are noncanonical, containing RR rather than RP, and in the case of MRTFB, RPEL1 terminates with QL rather than EL (6Cen B. Selvaraj A. Burgess R.C. Hitzler J.K. Ma Z. Morris S.W. Prywes R. Megakaryoblastic leukemia 1, a potent transcriptional coactivator for serum response factor (SRF), is required for serum induction of SRF target genes.Mol. Cell Biol. 2003; 23: 6597-6608Crossref PubMed Scopus (248) Google Scholar, 12Mizuguchi M. Fuju T. Obita T. Ishikawa M. Tsuda M. Tabuchi A. Transient alpha-helices in the disordered RPEL motifs of the serum response factor coactivator MKL1.Sci. Rep. 2014; 4: 5224Crossref PubMed Scopus (9) Google Scholar, 13Miralles F. Posern G. Zaromytidou A.I. Treisman R. Actin dynamics control SRF activity by regulation of its coactivator MAL.Cell. 2003; 113: 329-342Abstract Full Text Full Text PDF PubMed Scopus (1051) Google Scholar). Overall, MRTFA and MRTFB are 51% similar; the addition of 71 amino acids to the N-terminal end of MRTFB may increase its transcriptional activation activity (5Gilles L. Bluteau D. Boukour S. Chang Y. Zhang Y. Robert T. Dessen P. Debili N. Bernard O.A. Vainchenker W. Raslova H. MAL/SRF complex is involved in platelet formation and megakaryocyte migration by regulating MYL9 (MLC2) and MMP9.Blood. 2009; 114: 4221-4232Crossref PubMed Scopus (62) Google Scholar). All three coactivate SRF in a basic domain-dependent manner, though myocardin also requires the Q domain (6Cen B. Selvaraj A. Burgess R.C. Hitzler J.K. Ma Z. Morris S.W. Prywes R. Megakaryoblastic leukemia 1, a potent transcriptional coactivator for serum response factor (SRF), is required for serum induction of SRF target genes.Mol. Cell Biol. 2003; 23: 6597-6608Crossref PubMed Scopus (248) Google Scholar, 7Cen B. Selvaraj A. Prywes R. Myocardin/MKL family of SRF coactivators: Key regulators of immediate early and muscle specific gene expression.J. Cell Biochem. 2004; 93: 74-82Crossref PubMed Scopus (135) Google Scholar). Additionally, all myocardin family proteins can form homodimers or heterodimers with each other with the ability to dimerize being more critical for myocardin function than either MRTFA or MRTFB (24Sasazuki T. Sawada T. Sakon S. Kitamura T. Kishi T. Okazaki T. Katano M. Tanaka M. Watanabe M. Yagita H. Okumura K. Nakano H. Identification of a novel transcriptional activator, BSAC, by a functional cloning to inhibit tumor necrosis factor-induced cell death.J. Biol. Chem. 2002; 277: 28853-28860Abstract Full Text Full Text PDF PubMed Scopus (82) Google Scholar, 25Sawada T. Nishiyama C. Kishi T. Sasazuki T. Komazawa-Sakon S. Xue X. Piao J.H. Ogata H. Nakayama J. Taki T. Hayashi Y. Watanabe M. Yagita H. Okumura K. Nakano H. Fusion of OTT to BSAC results in aberrant up-regulation of transcriptional activity.J. Biol. Chem. 2008; 283: 26820-26828Abstract Full Text Full Text PDF PubMed Scopus (14) Google Scholar). While myocardin is expressed primarily in cardiac and smooth muscle cells, MRTFA and MRTFB are ubiquitously expressed (6Cen B. Selvaraj A. Burgess R.C. Hitzler J.K. Ma Z. Morris S.W. Prywes R. Megakaryoblastic leukemia 1, a potent transcriptional coactivator for serum response factor (SRF), is required for serum induction of SRF target genes.Mol. Cell Biol. 2003; 23: 6597-6608Crossref PubMed Scopus (248) Google Scholar, 7Cen B. Selvaraj A. Prywes R. Myocardin/MKL family of SRF coactivators: Key regulators of immediate early and muscle specific gene expression.J. Cell Biochem. 2004; 93: 74-82Crossref PubMed Scopus (135) Google Scholar). As well as sharing more than half of their amino acid sequence, MRTFA and MRTFB can compensate for one another functionally which is of particular importance to hematopoietic development (see MRTFA in megakaryopoiesis). Most of what is known regarding regulation of MRTFA function occurs at the protein level; there is little to no information in the literature about transcriptional or translational regulation of MRTFA expression. Investigation of MRTFA gene regulation could be an area of fruitful research shedding light on its wider expression relative to myocardin. Posttranslational regulation of MRTFA includes its binding to G-actin, which affects cellular localization and function. Upon activation by membrane receptors and/or mechanical stimuli, signaling via RhoA and/or other G-proteins indirectly regulates MRTFA localization by promoting formin-mediated actin polymerization (13Miralles F. Posern G. Zaromytidou A.I. Treisman R. Actin dynamics control SRF activity by regulation of its coactivator MAL.Cell. 2003; 113: 329-342Abstract Full Text Full Text PDF PubMed Scopus (1051) Google Scholar, 26Hill C.S. Wynne J. Treisman R. The Rho family GTPases RhoA, Rac1, and CDC42Hs regulate transcriptional activation by SRF.Cell. 1995; 81: 1159-1170Abstract Full Text PDF PubMed Scopus (1205) Google Scholar, 27Ridley A.J. Hall A. The small GTP-binding protein rho regulates the assembly of focal adhesions and actin stress fibers in response to growth f" @default.
• W3136692316 created "2021-03-29" @default.
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• W3136692316 date "2021-01-01" @default.
• W3136692316 modified "2023-10-14" @default.
• W3136692316 title "MRTFA: A critical protein in normal and malignant hematopoiesis and beyond" @default.
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• W3136692316 doi "https://doi.org/10.1016/j.jbc.2021.100543" @default.
• W3136692316 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/8079280" @default.
• W3136692316 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/33722605" @default.
• W3136692316 hasPublicationYear "2021" @default.

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