Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi

MAP/Microtubule Affinity-Regulating Kinase

  • Elizabeth Tang
  • C. Yan ChengEmail author
Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_101717


Historical Background

Microtubule-associated protein (MAP)/microtubule affinity-regulating kinase [MARK] was first identified for its role in phosphorylating tau, a MAP implicated in Alzheimer’s disease [AD] (Drewes et al. 1995). Following this discovery, four MARK isoforms were identified in humans and rodents, all of which phosphorylate tau, MAP2, and MAP4 (Drewes et al. 1995; Illenberger et al. 1996; Drewes 2004). Phosphorylation of MAPs causes them to dissociate from microtubules [MTs] leading to MT destabilization (Drewes et al. 1997, 1998). Tau has been the subject of intensive studies because its phosphorylation is elevated in the AD brain. Since MARK phosphorylates tau, it is a candidate of prime interest as a possible therapeutic target in treating AD and other brain disorders (Drewes 2004; Naz et al. 2013). MARK has also been found to be...

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This work was supported by grants from the National Institutes of Health, NICHD, R01 HD056034 to C.Y.C., and U54 HD029990 Project 5 to C.Y.C.


  1. Al-Hakim AK, Zagorska A, Chapman L, Deak M, Peggie M, Alessi DR. Control of AMPK-related kinases by USP9X and atypical Lys(29)/Lys(33)-linked polyubiquitin chains. Biochem J. 2008;411:249–60. doi:10.1042/BJ20080067.CrossRefPubMedGoogle Scholar
  2. Bessone S, Vidal F, Le Bouc Y, Epelbaum J, Bluet-Pajot MT, Darmon M. EMK protein kinase-null mice: dwarfism and hypofertility associated with alterations in the somatotrope and prolactin pathways. Dev Biol. 1999;214:87–101. doi:10.1006/dbio.1999.9379.CrossRefPubMedGoogle Scholar
  3. Black MM. Axonal transport: the orderly motion of axonal structures. Methods Cell Biol. 2016;131:1–19.CrossRefPubMedGoogle Scholar
  4. Cheng CY. Toxicants target cell junctions in the testis – insights from the indazole-carboxylic acid model. Spermatogenesis. 2014;4:e981485. doi:10.4161/21565562.2014.9814895.CrossRefPubMedGoogle Scholar
  5. Cheng CY, Mruk DD, Silvestrini B, Bonanomi M, Wong CH, Siu MKY, et al. AF-2364 [1-(2,4-dichlorobenzyl)-1H-indazole-3-carbohydrazide] is a potential male contraceptive: A review of recent data. Contraception. 2005;72:251–61.CrossRefPubMedGoogle Scholar
  6. Desai A, Mitchison TJ. Microtubule polymerization dynamics. Annu Rev Cell Dev Biol. 1997;13:83–117. doi:10.1146/annurev.cellbio.13.1.83.CrossRefPubMedGoogle Scholar
  7. Drewes G. MARKing tau for tangles and toxicity. Trends Biochem Sci. 2004;29:548–55.CrossRefPubMedGoogle Scholar
  8. Drewes G, Ebneth A, Mandelkow EM. MAPs, MARKs and microtubule dynamics. Trends Biochem Sci. 1998;23:307–11.CrossRefPubMedGoogle Scholar
  9. Drewes G, Ebneth A, Preuss U, Mandelkow EM, Mandelkow E. MARK, a novel family of protein kinases that phosphorylate microtubule-associated proteins and trigger microtubule disruption. Cell. 1997;89:297–308.CrossRefPubMedGoogle Scholar
  10. Drewes G, Trinczek B, Illenberger S, Biernat J, Schmitt-Ulms G, Meyer HE, et al. Microtubule-associated protein/microtubule affinity-regulating kinase (p110mark). A novel protein kinase that regulates tau-microtubule interactions and dynamic instability by phosphorylation at the Alzheimer-specific site serine 262. J Biol Chem. 1995;270:7679–88.CrossRefPubMedGoogle Scholar
  11. Elbert M, Rossi G, Brennwald P. The yeast par-1 homologs kin1 and kin2 show genetic and physical interactions with components of the exocytic machinery. Mol Biol Cell. 2005;16:532–49. doi:10.1091/mbc.E04-07-0549.CrossRefPubMedPubMedCentralGoogle Scholar
  12. Fabbri M, Rosa MM, Abreu D, Ferreira JJ. Clinical pharmacology review of salinamide for the treatment of Parkinson’s disease. Neurodegener Dis Manag. 2015;5:481–96.CrossRefPubMedGoogle Scholar
  13. Folstein SE, Rosen-Sheidley B. Genetics of autism: complex aetiology for a heterogeneous disorder. Nat Rev Genet. 2001;2:943–55. doi:10.1038/35103559.CrossRefPubMedGoogle Scholar
  14. Gao Y, Xiao X, Lui WY, Lee WM, Mruk D, Cheng CY. Cell polarity proteins and spermatogenesis. Semin Cell Dev Biol. 2016;59:62–70. doi:10.1016/j.semcdb.2016.06.008.CrossRefPubMedPubMedCentralGoogle Scholar
  15. Goldstein B, Macara IG. The PAR proteins: fundamental players in animal cell polarization. Dev Cell. 2007;13:609–22.PubMedPubMedCentralCrossRefGoogle Scholar
  16. Hubaux R, Thu KL, Vucic EA, Pikor LA, Kung SH, Martinez VD, et al. Microtubule affinity-regulating kinase 2 is associated with DNA damage response and cisplatin resistance in non-small cell lung cancer. Int J Cancer. 2015;137:2072–82. doi:10.1002/ijc.29577.CrossRefPubMedPubMedCentralGoogle Scholar
  17. Hurov J, Piwnica-Worms H. The Par-1/MARK family of protein kinases: from polarity to metabolism. Cell Cycle. 2007;6:1966–9. doi:10.4161/cc.6.16.4576.CrossRefPubMedCentralPubMedGoogle Scholar
  18. Hurov JB, Stappenbeck TS, Zmasek CM, White LS, Ranganath SH, Russell JH, et al. Immune system dysfunction and autoimmune disease in mice lacking Emk (Par-1) protein kinase. Mol Cell Biol. 2001;21:3206–19. doi:10.1128/MCB.21.9.3206-3219.2001.CrossRefPubMedPubMedCentralGoogle Scholar
  19. Hurov JB, Watkins JL, Piwnica-Worms H. Atypical PKC phosphorylates PAR-1 kinases to regulate localization and activity. Curr Biol. 2004;14:736–41. doi:10.1016/j.cub.2004.04.007.CrossRefPubMedCentralPubMedGoogle Scholar
  20. Hutsler JJ, Zhang H. Increased dendritic spine densities on cortical projection neurons in autism spectrum disorders. Brain Res. 2010;1309:83–94. doi:10.1016/j.brainres.2009.09.120.CrossRefPubMedGoogle Scholar
  21. Illenberger S, Drewes G, Trinczek B, Biernat J, Meyer HE, Olmsted JB, et al. Phosphorylation of microtubule-associated proteins MAP2 and MAP4 by the protein kinase p110mark. Phosphorylation sites and regulation of microtubule dynamics. J Biol Chem. 1996;271:10834–43.CrossRefPubMedGoogle Scholar
  22. Johne C, Matenia D, Li XY, Timm T, Balusamy K, Mandelkow EM. Spred1 and TESK1--two new interaction partners of the kinase MARKK/TAO1 that link the microtubule and actin cytoskeleton. Mol Biol Cell. 2008;19:1391–403. doi:10.1091/mbc.E07-07-0730.CrossRefPubMedPubMedCentralGoogle Scholar
  23. Kato T, Satoh S, Okabe H, Kitahara O, Ono K, Kihara C, et al. Isolation of a novel human gene, MARKL1, homologous to MARK3 and its involvement in hepatocellular carcinogenesis. Neoplasia. 2001;3:4–9. doi:10.1038/sj/neo/7900132.CrossRefPubMedPubMedCentralGoogle Scholar
  24. Kemphues K. PARsing embryonic polarity. Cell. 2000;101:345–8.PubMedPubMedCentralCrossRefGoogle Scholar
  25. Laplante M, Sabatini DM. mTOR signaling at a glance. J Cell Sci. 2009;122:3589–94. doi:10.1242/jcs.051011.CrossRefPubMedPubMedCentralGoogle Scholar
  26. Lennerz JK, Hurov JB, White LS, Lewandowski KT, Prior JL, Planer GJ, et al. Loss of Par-1a/MARK3/C-TAK1 kinase leads to reduced adiposity, resistance to hepatic steatosis, and defective gluconeogenesis. Mol Cell Biol. 2010;30:5043–56. doi:10.1128/MCB.01472-09.CrossRefPubMedPubMedCentralGoogle Scholar
  27. Liu Z, Gan L, Chen Y, Luo D, Zhang Z, Cao W, et al. Mark4 promotes oxidative stress and inflammation via binding to PPARgamma and activating NF-kappaB pathway in mice adipocytes. Sci Rep. 2016;6:21382. doi:10.1038/srep21382.CrossRefPubMedPubMedCentralGoogle Scholar
  28. Lizcano JM, Goransson O, Toth R, Deak M, Morrice NA, Boudeau J, et al. LKB1 is a master kinase that activates 13 kinases of the AMPK subfamily, including MARK/PAR-1. EMBO J. 2004;23:833–43. doi:10.1038/sj.emboj.7600110.CrossRefPubMedPubMedCentralGoogle Scholar
  29. Magnani I, Novielli C, Fontana L, Tabano S, Rovina D, Moroni RF, et al. Differential signature of the centrosomal MARK4 isoforms in glioma. Anal Cell Pathol. 2011;34:319–38. doi:10.3233/ACP-2011-0031.CrossRefGoogle Scholar
  30. Mamidi A, Inui M, Manfrin A, Soligo S, Enzo E, Aragona M, et al. Signaling crosstalk between TGF beta and Dishevelled/Par1b. Cell Death Differ. 2012;19:1689–97. doi:10.1038/cdd.2012.50.CrossRefPubMedPubMedCentralGoogle Scholar
  31. Marx A, Nugoor C, Panneerselvam S, Mandelkow E. Structure and function of polarity-inducing kinase family MARK/Par-1 within the branch of AMPK/Snf1-related kinases. FASEB J. 2010;24:1637–48. doi:10.1096/fj.09-148064.CrossRefPubMedCentralPubMedGoogle Scholar
  32. Matenia D, Griesshaber B, Li XY, Thiessen A, Johne C, Jiao J, et al. PAK5 kinase is an inhibitor of MARK/Par-1, which leads to stable microtubules and dynamic actin. Mol Biol Cell. 2005;16:4410–22. doi:10.1091/mbc.E05-01-0081.CrossRefPubMedPubMedCentralGoogle Scholar
  33. Matenia D, Hempp C, Timm T, Eikhof A, Mandelkow EM. Microtubule affinity-regulating kinase 2 (MARK2) turns on phosphatase and tensin homolog (PTEN)-induced kinase 1 (PINK1) at Thr-313, a mutation site in Parkinson disease: effects on mitochondrial transport. J Biol Chem. 2012;287:8174–86. doi:10.1074/jbc.M111.262287.CrossRefPubMedPubMedCentralGoogle Scholar
  34. Matenia D, Mandelkow EM. Emerging modes of PINK1 signaling: another task for MARK2. Front Mol Neurosci. 2014;7:37. doi:10.3389/fnmol.2014.00037.CrossRefPubMedPubMedCentralGoogle Scholar
  35. Maussion G, Carayol J, Lepagnol-Bestel AM, Tores F, Loe-Mie Y, Milbreta U, et al. Convergent evidence identifying MAP/microtubule affinity-regulating kinase 1 (MARK1) as a susceptibility gene for autism. Hum Mol Genet. 2008;17:2541–51. doi:10.1093/hmg/ddn154.CrossRefPubMedGoogle Scholar
  36. McDonald JA. Canonical and noncanonical roles of Par-1/MARK kinases in cell migration. Int Rev Cell Mol Biol. 2014;312:169–99. doi:10.1016/B978-0-12-800178-3.00006-3.CrossRefPubMedGoogle Scholar
  37. Mitchison T, Kirschner M. Dynamic instability of microtubule growth. Nature. 1984;312:237–42.CrossRefGoogle Scholar
  38. Mohseni M, Sun J, Lau A, Curtis S, Goldsmith J, Fox VL, et al. A genetic screen identifies an LKB1-MARK signalling axis controlling the Hippo-YAP pathway. Nat Cell Biol. 2014;16:108–17. doi:10.1038/ncb2884.CrossRefPubMedGoogle Scholar
  39. Moravcevic K, Mendrola JM, Schmitz KR, Wang YH, Slochower D, Janmey PA, et al. Kinase associated-1 domains drive MARK/PAR1 kinases to membrane targets by binding acidic phospholipids. Cell. 2010;143:966–77. doi:10.1016/j.cell.2010.11.028.CrossRefPubMedPubMedCentralGoogle Scholar
  40. Mruk DD, Cheng CY. Sertoli-Sertoli and Sertoli-germ cell interactions and their significance in germ cell movement in the seminiferous epithelium during spermatogenesis. Endocr Rev. 2004;25:747–806.PubMedPubMedCentralCrossRefGoogle Scholar
  41. Muller J, Ritt DA, Copeland TD, Morrison DK. Functional analysis of C-TAK1 substrate binding and identification of PKP2 as a new C-TAK1 substrate. EMBO J. 2003;22:4431–42. doi:10.1093/emboj/cdg426.CrossRefPubMedPubMedCentralGoogle Scholar
  42. Murphy JM, Korzhnev DM, Ceccarelli DF, Briant DJ, Zarrine-Afsar A, Sicheri F, et al. Conformational instability of the MARK3 UBA domain compromises ubiquitin recognition and promotes interaction with the adjacent kinase domain. Proc Natl Acad Sci U S A. 2007;104:14336–41. doi:10.1073/pnas.0703012104.CrossRefPubMedPubMedCentralGoogle Scholar
  43. Naz F, Anjum F, Islam A, Ahmad F, Hassan MI. Microtubule affinity-regulating kinase 4: structure, function, and regulation. Cell Biochem Biophys. 2013;67:485–99. doi:10.1007/s12013-013-9550-7.CrossRefPubMedGoogle Scholar
  44. Ossipova O, Dhawan S, Sokol S, Green JB. Distinct PAR-1 proteins function in different branches of Wnt signaling during vertebrate development. Dev Cell. 2005;8:829–41. doi:10.1016/j.devcel.2005.04.011.CrossRefPubMedGoogle Scholar
  45. Peng CY, Graves PR, Ogg S, Thoma RS, Byrnes 3rd MJ, Wu Z, et al. C-TAK1 protein kinase phosphorylates human Cdc25C on serine 216 and promotes 14-3-3 protein binding. Cell Growth Differ. 1998;9:197–208.PubMedCentralPubMedGoogle Scholar
  46. Reiner O, Sapir T. Mark/Par-1 marking the polarity of migrating neurons. Adv Exp Med Biol. 2014;800:97–111. doi:10.1007/978-94-007-7687-6_6.CrossRefGoogle Scholar
  47. Rodriguez-Boulan E, Macara IG. Organization and execution of the epithelial polarity programme. Nat Rev Mol Cell Biol. 2014;15:225–42. doi:10.1038/nrm3775.CrossRefPubMedPubMedCentralGoogle Scholar
  48. Segu L, Pascaud A, Costet P, Darmon M, Buhot MC. Impairment of spatial learning and memory in ELKL Motif Kinase1 (EMK1/MARK2) knockout mice. Neurobiol Aging. 2008;29:231–40. doi:10.1016/j.neurobiolaging.2006.10.014.CrossRefPubMedGoogle Scholar
  49. Shulman JM, Benton R, St Johnston D. The Drosophila homolog of C. elegans PAR-1 organizes the oocyte cytoskeleton and directs oskar mRNA localization to the posterior pole. Cell. 2000;101:377–88.CrossRefPubMedGoogle Scholar
  50. Sun C, Tian L, Nie J, Zhang H, Han X, Shi Y. Inactivation of MARK4, an AMP-activated protein kinase (AMPK)-related kinase, leads to insulin hypersensitivity and resistance to diet-induced obesity. J Biol Chem. 2012;287:38305–15. doi:10.1074/jbc.M112.388934.CrossRefPubMedPubMedCentralGoogle Scholar
  51. Suzuki A, Hirata M, Kamimura K, Maniwa R, Yamanaka T, Mizuno K, et al. aPKC acts upstream of PAR-1b in both the establishment and maintenance of mammalian epithelial polarity. Curr Biol. 2004;14:1425–35. doi:10.1016/j.cub.2004.08.021.CrossRefGoogle Scholar
  52. Tang EI, Lee WM, Cheng CY. Coordination of actin- and microtubule-based cytoskeletons supports transport of spermatids and residual bodies/phagosomes during spermatogenesis in the rat testis. Endocrinology. 2016;157:1644–59. doi:10.1210/en.2015-1962.CrossRefPubMedPubMedCentralGoogle Scholar
  53. Tang EI, Mruk DD, Cheng CY. MAP/microtubule affinity-regulating kinases, microtubule dynamics, and spermatogenesis. J Endocrinol. 2013;217:R13–23.PubMedPubMedCentralCrossRefGoogle Scholar
  54. Tang EI, Xiao X, Mruk DD, Qian XJ, Mok KW, Jenardhanan P, et al. Microtubule affinity-regulating kinase 4 (MARK4) is a component of the ectoplasmic specialization in the rat testis. Spermatogenesis. 2012;2:117–26.PubMedPubMedCentralCrossRefGoogle Scholar
  55. Tang N, Chisholm A. Regulation of microtubule dynamics in axon regeneration: insights from C. elegans. F1000 Research. 2016; 5:F1000 Faculty Rev-764. doi:10.12688/f1000research.8197.1CrossRefGoogle Scholar
  56. Timm T, Balusamy K, Li X, Biernat J, Mandelkow E, Mandelkow EM. Glycogen synthase kinase (GSK) 3beta directly phosphorylates Serine 212 in the regulatory loop and inhibits microtubule affinity-regulating kinase (MARK) 2. J Biol Chem. 2008;283:18873–82. doi:10.1074/jbc.M706596200.CrossRefPubMedGoogle Scholar
  57. Uboha NV, Flajolet M, Nairn AC, Picciotto MR. A calcium- and calmodulin-dependent kinase Ialpha/microtubule affinity regulating kinase 2 signaling cascade mediates calcium-dependent neurite outgrowth. J Neurosci. 2007;27:4413–23. doi:10.1523/JNEUROSCI.0725-07.2007.CrossRefPubMedGoogle Scholar
  58. Wu ZZ, Lu HP, Chao CC. Identification and functional analysis of genes which confer resistance to cisplatin in tumor cells. Biochem Pharmacol. 2010;80:262–76. doi:10.1016/j.bcp.2010.03.029.CrossRefPubMedGoogle Scholar

Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.The Mary M. Wohlford Laboratory for Male Contraceptive Research, Center for Biomedical Research, Population CouncilNew YorkUSA