Myotonin-protein kinase

Available structures
PDBOrtholog search: PDBe RCSB
Aliases DMPK, DM, DM1, DM1PK, DMK, MDPK, MT-PK, Dm15, dystrophia myotonica protein kinase
External IDs MGI: 94906 HomoloGene: 3247 GeneCards: DMPK
RNA expression pattern

More reference expression data
Species Human Mouse









RefSeq (mRNA)


RefSeq (protein)


Location (UCSC) Chr 19: 45.77 – 45.78 Mb Chr 7: 19.08 – 19.09 Mb
PubMed search [1] [2]
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Myotonin-protein kinase (MT-PK) also known as myotonic dystrophy protein kinase (MDPK) or dystrophia myotonica protein kinase (DMK) is an enzyme that in humans is encoded by the DMPK gene.[3][4][5]

The dmpk gene product is a Ser/Thr protein kinase homologous to the MRCK p21-activated kinases and the Rho family of kinases.[6] Data obtained by using antibodies that detect specific isoforms of DMPK indicate that the most abundant isoform of DMPK is an 80-kDa protein expressed almost exclusively in smooth, skeletal, and cardiac muscles.[7] This kinase exists both as a membrane-associated and as a soluble form in human left ventricular samples. The different C termini of DMPK that arise from alternative splicing determine its localization to the endoplasmic reticulum, mitochondria, or cytosol in transfected COS-1 cells.[8] ). Among the substrates for DMPK proposed by in vitro studies are phospholemman, the dihydropyridine receptor, and the myosin phosphatase targeting subunit. However, an in vivo demonstration of the phosphorylation of these substrates by DMPK remains to be established, and a link between these substrates and the clinical manifestations of DM is unclear.[9][10]


Myotonin-protein kinase is a serine-threonine kinase that is closely related to other kinases that interact with members of the Rho family of small GTPases. Substrates for this enzyme include myogenin, the beta-subunit of the L-type calcium channels, and phospholemman.[5] Although the specific function of this protein is unknown, it appears to play an important role in muscle, heart, and brain cells. This protein may be involved in communication within cells. It also appears to regulate the production and function of important structures inside muscle cells by interacting with other proteins. For example, myotonic dystrophy protein kinase has been shown to turn off (inhibit) part of a muscle protein called myosin phosphatase. Myosin phosphatase is an enzyme that plays a role in muscle tensing (contraction) and relaxation.[11]


Dystrophia myotonica protein kinase (DMPK) is a serine/threonine kinase composed of a kinase domain and a coiled-coil domain involved in the multimerization. The crystal structure of the kinase domain of DMPK bound to the inhibitor bisindolylmaleimide VIII (BIM-8) revealed a dimeric enzyme associated by a conserved dimerization domain. The affinity of dimerisation suggested that the kinase domain alone is insufficient for dimerisation in vivo and that the coiled-coil domains are required for stable dimer formation. The kinase domain is in an active conformation, with a fully ordered and correctly positioned aC helix, and catalytic residues in a conformation competent for catalysis. The conserved hydrophobic motif at the C-terminal extension of the kinase domain is bound to the N-terminal lobe of the kinase domain, despite being unphosphorylated.[12]

Clinical significance

The 3' untranslated region of this gene contains 5-37 copies of a CTG trinucleotide repeat. Expansion of this unstable motif to 50-5,000 copies causes myotonic dystrophy type I, which increases in severity with increasing repeat element copy number. Repeat expansion is associated with condensation of local chromatin structure that disrupts the expression of genes in this region. As shown in the figure, as the DMPK repeat is replicated, the hairpin loop that is formed leads to repeat expansion (a) or contractions (b).[5]

CTG repeats are located in the 3' UTR of the DMPK gene. Through formation of hairpin loops, the repeats are contracted or expanded.

Myotonic dystrophy (DM) 1 is an autosomal dominant neuromuscular disorder affecting approximately 1 in 8000 individuals. Affected individuals display a wide range of symptoms including myotonia, skeletal muscle weakness and wasting, cardiac conduction abnormalities, and cataracts. Despite cloning of the locus, the complex disease phenotype of DM has proven difficult to interpret, and the exact role of DMPK in the pathogenesis of DM remains unclear.[13]


Myotonic dystrophy protein kinase has been shown to interact with HSPB2[14][15] and RAC1.[16]


The close relationship of DMPK to the Rho-kinases has led to speculation whether DMPK activity may be regulated in vivo by small G proteins, particularly of the Rho family. Although DMPK lacks obvious binding sites for known G, DMPK-1 oligomers exhibit low basal catalytic activity due to the presence of the C-terminal autoinhibitory domain (AI). A protease (P) within the membrane cleaves DMPK-1, removing the C-terminal autoinhibitory and membrane association domains and releasing cytosolic, basally active DMPK-2. This processing event would produce longterm activation of the kinase. Short-term activation of DMPK-1 and -2 may be mediated by transitory interaction with a small GTPase (G).

A general model that accounts for DMPK oligomerization, processing, and regulation has been proposed. In this model, transient activation of kinase activity would occur in response to G protein second messengers, while longterm activation of DMPK could be mediated by a membrane associated protease that cleaves DMPK-1 to release cytosolic DMPK-2 in a persistently activated form. The persistent activation of serine/threonine kinases has been shown to play a role in the determination of cell fate as well as memory production in the nervous system. In this respect, DMPK may be similar to PKA and PKC, two kinases that can be transiently activated in response to second messengers or persistently activated by proteolytic removal of an autoinhibitory domain. Thus, this model suggests that the two endogenous DMPK forms may possess different activities, localizations, regulators, and substrates and perform distinct physiological functions.[17][18]


  1. "Human PubMed Reference:".
  2. "Mouse PubMed Reference:".
  3. Mahadevan M, Tsilfidis C, Sabourin L, Shutler G, Amemiya C, Jansen G, Neville C, Narang M, Barceló J, O'Hoy K (April 1992). "Myotonic dystrophy mutation: an unstable CTG repeat in the 3' untranslated region of the gene". Science. 255 (5049): 1253–5. doi:10.1126/science.1546325. PMID 1546325.
  4. Fu YH, Pizzuti A, Fenwick RG, King J, Rajnarayan S, Dunne PW, Dubel J, Nasser GA, Ashizawa T, de Jong P (April 1992). "An unstable triplet repeat in a gene related to myotonic muscular dystrophy". Science. 255 (5049): 1256–8. doi:10.1126/science.1546326. PMID 1546326.
  5. 1 2 3 "Entrez Gene: DMPK dystrophia myotonica-protein kinase".
  6. Amano M, Chihara K, Nakamura N, Kaneko T, Matsuura Y, Kaibuchi K (Nov 1999). "The COOH terminus of Rho-kinase negatively regulates rho-kinase activity". The Journal of Biological Chemistry. 274 (45): 32418–24. doi:10.1074/jbc.274.45.32418. PMID 10542285.
  7. Lam LT, Pham YC, Nguyen TM, Morris GE (Sep 2000). "Characterization of a monoclonal antibody panel shows that the myotonic dystrophy protein kinase, DMPK, is expressed almost exclusively in muscle and heart". Human Molecular Genetics. 9 (14): 2167–73. doi:10.1093/hmg/9.14.2167. PMID 10958655.
  8. Wansink DG, van Herpen RE, Coerwinkel-Driessen MM, Groenen PJ, Hemmings BA, Wieringa B (Aug 2003). "Alternative splicing controls myotonic dystrophy protein kinase structure, enzymatic activity, and subcellular localization". Molecular and Cellular Biology. 23 (16): 5489–501. doi:10.1128/mcb.23.16.5489-5501.2003. PMID 12897125.
  9. Timchenko L, Nastainczyk W, Schneider T, Patel B, Hofmann F, Caskey CT (Jun 1995). "Full-length myotonin protein kinase (72 kDa) displays serine kinase activity". Proceedings of the National Academy of Sciences of the United States of America. 92 (12): 5366–70. doi:10.1073/pnas.92.12.5366. PMID 7777513.
  10. Kaliman P, Catalucci D, Lam JT, Kondo R, Gutiérrez JC, Reddy S, Palacín M, Zorzano A, Chien KR, Ruiz-Lozano P (Mar 2005). "Myotonic dystrophy protein kinase phosphorylates phospholamban and regulates calcium uptake in cardiomyocyte sarcoplasmic reticulum". The Journal of Biological Chemistry. 280 (9): 8016–21. doi:10.1074/jbc.M412845200. PMID 15598648.
  11. Missing or empty |title= (help)
  12. Elkins JM, Amos A, Niesen FH, Pike AC, Fedorov O, Knapp S (Apr 2009). "Structure of dystrophia myotonica protein kinase". Protein Science. 18 (4): 782–91. doi:10.1002/pro.82. PMID 19309729.
  13. Bush, Eric W. (May 9, 2000). "Myotonic Dystrophy Protein Kinase Domains Mediate Localization, Oligomerization, Novel Catalytic Activity, and Autoinhibition". Biochemistry. 39: 8480–8490. doi:10.1021/bi992142f. PMID 10913253.
  14. Suzuki A, Sugiyama Y, Hayashi Y, Nyu-i N, Yoshida M, Nonaka I, Ishiura S, Arahata K, Ohno S (March 1998). "MKBP, a novel member of the small heat shock protein family, binds and activates the myotonic dystrophy protein kinase". J. Cell Biol. UNITED STATES. 140 (5): 1113–24. doi:10.1083/jcb.140.5.1113. ISSN 0021-9525. PMC 2132705Freely accessible. PMID 9490724.
  15. Sugiyama Y, Suzuki A, Kishikawa M, Akutsu R, Hirose T, Waye MM, Tsui SK, Yoshida S, Ohno S (January 2000). "Muscle develops a specific form of small heat shock protein complex composed of MKBP/HSPB2 and HSPB3 during myogenic differentiation". J. Biol. Chem. 275 (2): 1095–104. doi:10.1074/jbc.275.2.1095. PMID 10625651.
  16. Shimizu M, Wang W, Walch ET, Dunne PW, Epstein HF (June 2000). "Rac-1 and Raf-1 kinases, components of distinct signaling pathways, activate myotonic dystrophy protein kinase". FEBS Lett. 475 (3): 273–7. doi:10.1016/S0014-5793(00)01692-6. PMID 10869570.
  17. Bush EW, Helmke SM, Birnbaum RA, Perryman MB (Jul 2000). "Myotonic dystrophy protein kinase domains mediate localization, oligomerization, novel catalytic activity, and autoinhibition". Biochemistry. 39 (29): 8480–90. doi:10.1021/bi992142f. PMID 10913253.
  18. Edlund T, Jessell TM (Jan 1999). "Progression from extrinsic to intrinsic signaling in cell fate specification: a view from the nervous system". Cell. 96 (2): 211–24. doi:10.1016/s0092-8674(00)80561-9. PMID 9988216.

Further reading

  • Groenen P, Wieringa B (1999). "Expanding complexity in myotonic dystrophy.". BioEssays. 20 (11): 901–12. doi:10.1002/(SICI)1521-1878(199811)20:11<901::AID-BIES5>3.0.CO;2-0. PMID 9872056. 
  • Jansen G, Mahadevan M, Amemiya C, Wormskamp N, Segers B, Hendriks W, O'Hoy K, Baird S, Sabourin L, Lennon G (1993). "Characterization of the myotonic dystrophy region predicts multiple protein isoform-encoding mRNAs.". Nat. Genet. 1 (4): 261–6. doi:10.1038/ng0792-261. PMID 1302022. 
  • Tsilfidis C, MacKenzie AE, Mettler G, Barceló J, Korneluk RG (1993). "Correlation between CTG trinucleotide repeat length and frequency of severe congenital myotonic dystrophy.". Nat. Genet. 1 (3): 192–5. doi:10.1038/ng0692-192. PMID 1303233. 
  • Brook JD, McCurrach ME, Harley HG, Buckler AJ, Church D, Aburatani H, Hunter K, Stanton VP, Thirion JP, Hudson T (1992). "Molecular basis of myotonic dystrophy: expansion of a trinucleotide (CTG) repeat at the 3' end of a transcript encoding a protein kinase family member.". Cell. 68 (4): 799–808. doi:10.1016/0092-8674(92)90154-5. PMID 1310900. 
  • Harley HG, Walsh KV, Rundle S, Brook JD, Sarfarazi M, Koch MC, Floyd JL, Harper PS, Shaw DJ (1991). "Localisation of the myotonic dystrophy locus to 19q13.2-19q13.3 and its relationship to twelve polymorphic loci on 19q.". Hum. Genet. 87 (1): 73–80. doi:10.1007/BF01213096. PMID 2037285. 
  • Gennarelli M, Lucarelli M, Zelano G, Pizzuti A, Novelli G, Dallapiccola B (1995). "Different expression of the myotonin protein kinase gene in discrete areas of human brain.". Biochem. Biophys. Res. Commun. 216 (2): 489–94. doi:10.1006/bbrc.1995.2649. PMID 7488138. 
  • Shaw DJ, McCurrach M, Rundle SA, Harley HG, Crow SR, Sohn R, Thirion JP, Hamshere MG, Buckler AJ, Harper PS (1994). "Genomic organization and transcriptional units at the myotonic dystrophy locus.". Genomics. 18 (3): 673–9. doi:10.1016/S0888-7543(05)80372-6. PMID 7905855. 
  • Sasagawa N, Sorimachi H, Maruyama K, Arahata K, Ishiura S, Suzuki K (1994). "Expression of a novel human myotonin protein kinase (MtPK) cDNA clone which encodes a protein with a thymopoietin-like domain in COS cells.". FEBS Lett. 351 (1): 22–6. doi:10.1016/0014-5793(94)00808-6. PMID 8076686. 
  • van der Ven PF, Jansen G, van Kuppevelt TH, Perryman MB, Lupa M, Dunne PW, ter Laak HJ, Jap PH, Veerkamp JH, Epstein HF (1994). "Myotonic dystrophy kinase is a component of neuromuscular junctions.". Hum. Mol. Genet. 2 (11): 1889–94. doi:10.1093/hmg/2.11.1889. PMID 8281152. 
  • Carango P, Noble JE, Marks HG, Funanage VL (1994). "Absence of myotonic dystrophy protein kinase (DMPK) mRNA as a result of a triplet repeat expansion in myotonic dystrophy.". Genomics. 18 (2): 340–8. doi:10.1006/geno.1993.1474. PMID 8288237. 
  • Jansen G, Bartolomei M, Kalscheuer V, Merkx G, Wormskamp N, Mariman E, Smeets D, Ropers HH, Wieringa B (1993). "No imprinting involved in the expression of DM-kinase mRNAs in mouse and human tissues.". Hum. Mol. Genet. 2 (8): 1221–7. doi:10.1093/hmg/2.8.1221. PMID 8401505. 
  • Fu YH, Friedman DL, Richards S, Pearlman JA, Gibbs RA, Pizzuti A, Ashizawa T, Perryman MB, Scarlato G, Fenwick RG (1993). "Decreased expression of myotonin-protein kinase messenger RNA and protein in adult form of myotonic dystrophy.". Science. 260 (5105): 235–8. doi:10.1126/science.8469976. PMID 8469976. 
  • Mahadevan MS, Amemiya C, Jansen G, Sabourin L, Baird S, Neville CE, Wormskamp N, Segers B, Batzer M, Lamerdin J (1993). "Structure and genomic sequence of the myotonic dystrophy (DM kinase) gene.". Hum. Mol. Genet. 2 (3): 299–304. doi:10.1093/hmg/2.3.299. PMID 8499920. 
  • Boucher CA, King SK, Carey N, Krahe R, Winchester CL, Rahman S, Creavin T, Meghji P, Bailey ME, Chartier FL (1996). "A novel homeodomain-encoding gene is associated with a large CpG island interrupted by the myotonic dystrophy unstable (CTG)n repeat.". Hum. Mol. Genet. 4 (10): 1919–25. doi:10.1093/hmg/4.10.1919. PMID 8595416. 
  • Roberts R, Timchenko NA, Miller JW, Reddy S, Caskey CT, Swanson MS, Timchenko LT (1998). "Altered phosphorylation and intracellular distribution of a (CUG)n triplet repeat RNA-binding protein in patients with myotonic dystrophy and in myotonin protein kinase knockout mice.". Proc. Natl. Acad. Sci. U.S.A. 94 (24): 13221–6. doi:10.1073/pnas.94.24.13221. PMC 24290Freely accessible. PMID 9371827. 
  • Suzuki A, Sugiyama Y, Hayashi Y, Nyu-i N, Yoshida M, Nonaka I, Ishiura S, Arahata K, Ohno S (1998). "MKBP, a novel member of the small heat shock protein family, binds and activates the myotonic dystrophy protein kinase.". J. Cell Biol. 140 (5): 1113–24. doi:10.1083/jcb.140.5.1113. PMC 2132705Freely accessible. PMID 9490724. 
  • Pham YC, Man N, Lam LT, Morris GE (1998). "Localization of myotonic dystrophy protein kinase in human and rabbit tissues using a new panel of monoclonal antibodies.". Hum. Mol. Genet. 7 (12): 1957–65. doi:10.1093/hmg/7.12.1957. PMID 9811941. 
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