Historical Background
Microtubules (MTs) are regulated by a large number of proteins and factors. One of the classes of protein that act as a regulator of microtubules are microtubule-associated proteins (MAPs) like tau, MAP2, and MAP4 (Mandelkow and Mandelkow 1995). MAPs are widely found in the brain of vertebrates and have been studied in detail (Illenberger et al. 1996). The protein kinases like MAP/microtubule-affinity regulating kinases (MARK) phosphorylate these MAPs and regulate their activity (Drewes et al. 1997).
Microtubule-affinity regulating kinase 4 (MARK4) was first discovered in the brain of Alzheimer’s disease (AD) patients. Overexpressed MARK4 phosphorylates tau on Ser262 in the microtubule-binding domain, present within...
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References
Baas PW. Microtubule transport in the axon. Int Rev Cytol 2002;212:41–62.
Beghini A, Magnani I, Roversi G, Piepoli T, Di Terlizzi S, Moroni RF, et al. The neural progenitor-restricted isoform of the MARK4 gene in 19q13.2 is upregulated in human gliomas and overexpressed in a subset of glioblastoma cell lines. Oncogene. 2003;22:2581–2591.
Biernat J, Wu YZ, Timm T, Zheng-Fischhofer Q, Mandelkow E, Meijer L, et al. Protein kinase MARK/PAR-1 is required for neurite outgrowth and establishment of neuronal polarity. Mol Biol Cell 2002;13:4013–4028. https://doi.org/10.1091/mbc.02-03-0046.
Brennan KR, Brown AM. Wnt proteins in mammary development and cancer. J Mammary Gland Biol Neoplasia 2004;9:119–131. https://doi.org/10.1023/B:JOMG.0000037157.94207.33 490061 [pii].
Bright NJ, Thornton C, Carling D. The regulation and function of mammalian AMPK-related kinases. Acta Physiol (Oxf). 2009;196:15–26. https://doi.org/10.1111/j.1748-1716.2009.01971.x APS1971 [pii].
D’Angelo A, Franco B. The dynamic cilium in human diseases. PathoGenetics 2009;2:3. https://doi.org/10.1186/1755-8417-2-3 1755-8417-2-3 [pii].
Dehmelt L, Halpain S. The MAP2/Tau family of microtubule-associated proteins. Genome Biol. 2005;6:204 https://doi.org/10.1186/gb-2004-6-1-204, gb-2004-6-1-204 [pii].
Dequiedt F, Martin M, Von Blume J, Vertommen D, Lecomte E, Mari N, et al. New role for hPar-1 kinases EMK and C-TAK1 in regulating localization and activity of class IIa histone deacetylases. Mol Cell Biol. 2006;26:7086–7102. https://doi.org/10.1128/MCB.00231-06, 26/19/7086 [pii].
Drewes G. MARKing tau for tangles and toxicity. Trends Biochem Sci 2004;29:548–555. https://doi.org/10.1016/j.tibs.2004.08.001 S0968-0004(04)00202-6 [pii].
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. doi:S0092-8674(00)80208-1 [pii].
Ebneth A, Drewes G, Mandelkow EM, Mandelkow E. Phosphorylation of MAP2c and MAP4 by MARK kinases leads to the destabilization of microtubules in cells. Cell Motil Cytoskeleton 1999;44:209–224. https://doi.org/10.1002/(SICI)1097-0169(199911)44:3<209::AID-CM6>3.0.CO;2-4.
Ertych N, Stolz A, Stenzinger A, Weichert W, Kaulfuss S, Burfeind P, et al. Increased microtubule assembly rates influence chromosomal instability in colorectal cancer cells. Nat Cell Biol 2014;16:779–791. https://doi.org/10.1038/ncb2994 ncb2994 [pii].
Etienne-Manneville S. From signaling pathways to microtubule dynamics: the key players. Curr Opin Cell Biol 2010;22:104–111. https://doi.org/10.1016/j.ceb.2009.11.008 S0955-0674(09)00214-2 [pii].
Feng M, Tian L, Gan L, Liu Z, Sun C. Mark4 promotes adipogenesis and triggers apoptosis in 3 T3-L1 adipocytes by activating JNK1 and inhibiting p38MAPK pathways. Biol Cell 2014;106:294–307. https://doi.org/10.1111/boc.201400004.
Gabrovska PN, Smith RA, Tiang T, Weinstein SR, Haupt LM, Griffiths LR. Development of an eight gene expression profile implicating human breast tumours of all grade. Mol Biol Rep 2012;39:3879–3892. https://doi.org/10.1007/s11033-011-1167-6.
Graser S, Stierhof YD, Lavoie SB, Gassner OS, Lamla S, Le Clech M, et al. Cep164, a novel centriole appendage protein required for primary cilium formation. J Cell Biol. 2007;179:321–330. https://doi.org/10.1083/jcb.200707181 jcb.200707181 [pii].
Gray KA, Yates B, Seal RL, Wright MW, Bruford EA. Genenames.org: the HGNC resources in 2015. Nucleic Acids Res 2015;43:D1079–D1085. https://doi.org/10.1093/nar/gku1071 gku1071 [pii].
Grundke-Iqbal I, Iqbal K, Tung YC, Quinlan M, Wisniewski HM, Binder LI. Abnormal phosphorylation of the microtubule-associated protein tau (tau) in Alzheimer cytoskeletal pathology. Proc Natl Acad Sci U S A 1986;83:4913–4917.
Guo S, Kemphues KJ. par-1, a gene required for establishing polarity in C. elegans embryos, encodes a putative Ser/Thr kinase that is asymmetrically distributed. Cell. 1995;81:611–620. doi:0092-8674(95)90082-9 [pii].
Hagiwara H, Yorifuji H, Sato-Yoshitake R, Hirokawa N. Competition between motor molecules (kinesin and cytoplasmic dynein) and fibrous microtubule-associated proteins in binding to microtubules. J Biol Chem 1994;269:3581–3589.
Hanks SK. Genomic analysis of the eukaryotic protein kinase superfamily: a perspective. Genome Biol 2003;4:111.
Hartmann C, Johnk L, Kitange G, Wu Y, Ashworth LK, Jenkins RB, et al. Transcript map of the 3.7-Mb D19S112-D19S246 candidate tumor suppressor region on the long arm of chromosome 19. Cancer Res 2002;62:4100–4108.
He X, Semenov M, Tamai K, Zeng X. LDL receptor-related proteins 5 and 6 in Wnt/beta-catenin signaling: arrows point the way. Development 2004;131:1663–1677. https://doi.org/10.1242/dev.01117 131/8/1663 [pii].
Hernandez F, Lucas JJ, Avila J. GSK3 and tau: two convergence points in Alzheimer’s disease. J Alzheimers Dis 2013;33 Suppl 1:S141–S144. https://doi.org/10.3233/JAD-2012-129025 B5L9646H8H926U26 [pii].
Herrero J, Muffato M, Beal K, Fitzgerald S, Gordon L, Pignatelli M, et al. Ensembl comparative genomics resources. Database (Oxford). 2016. https://doi.org/10.1093/database/baw053 baw053 [pii].
Hurov JB, Watkins JL, Piwnica-Worms H. Atypical PKC phosphorylates PAR-1 kinases to regulate localization and activity. Curr Biol 2004;14:736–741. https://doi.org/10.1016/j.cub.2004.04.007 S0960982204002581 [pii].
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;271:10834–10843.
Ishikawa H, Marshall WF. Ciliogenesis: building the cell’s antenna. Nat Rev Mol Cell Biol 2011;12:222–234. https://doi.org/10.1038/nrm3085 nrm3085 [pii].
Jaleel M, Villa F, Deak M, Toth R, Prescott AR, Van Aalten DM, et al. The ubiquitin-associated domain of AMPK-related kinases regulates conformation and LKB1-mediated phosphorylation and activation. Biochem J. 2006;394:545–555. https://doi.org/10.1042/BJ20051844 BJ20051844 [pii].
Johnson LN, Noble ME, Owen DJ. Active and inactive protein kinases: structural basis for regulation. Cell 1996;85:149–158. S0092-8674(00)81092-2 [pii].
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. https://doi.org/10.1038/sj/neo/7900132.
Kemphues K. PARsing embryonic polarity. Cell 2000;101:345–348. S0092-8674(00)80844-2 [pii].
Kinzler KW, Vogelstein B. Life (and death) in a malignant tumour. Nature 1996;379:19–20. https://doi.org/10.1038/379019a0.
Kobayashi T, Tsang WY, Li J, Lane W, Dynlacht BD. Centriolar kinesin Kif24 interacts with CP110 to remodel microtubules and regulate ciliogenesis. Cell 2011;145:914–925. https://doi.org/10.1016/j.cell.2011.04.028 S0092-8674(11)00486-7 [pii].
Kojima Y, Miyoshi H, Clevers HC, Oshima M, Aoki M, Taketo MM. Suppression of tubulin polymerization by the LKB1-microtubule-associated protein/microtubule affinity-regulating kinase signaling. J Biol Chem. 2007;282:23532–23540. https://doi.org/10.1074/jbc.M700590200 M700590200 [pii].
Kuhns S, Schmidt KN, Reymann J, Gilbert DF, Neuner A, Hub B, et al. The microtubule affinity regulating kinase MARK4 promotes axoneme extension during early ciliogenesis. J Cell Biol 2013;200:505–522. https://doi.org/10.1083/jcb.201206013 jcb.201206013 [pii].
Levin DE, Bishop JM. A putative protein kinase gene (kin1+) is important for growth polarity in Schizosaccharomyces pombe. Proc Natl Acad Sci USA 1990;87:8272–8276.
Li L, Guan KL. Microtubule-associated protein/microtubule affinity-regulating kinase 4 (MARK4) is a negative regulator of the mammalian target of rapamycin complex 1 (mTORC1). J Biol Chem 2013;288:703–708. https://doi.org/10.1074/jbc.C112.396903 C112.396903 [pii].
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;23:833–843. https://doi.org/10.1038/sj.emboj.7600110 7600110 [pii].
Lodish H, Berk A, Zipursky SL, Matsudaira P, Baltimore D, Darnell J. Microtubule dynamics and associated proteins. In: Molecular cell biology. 4th ed. New York: W. H. Freeman; 2000.
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 (Amst) 2011;34:319–338. https://doi.org/10.3233/ACP-2011-0031 9G128517N2610886[pii].
Mandelkow E, Mandelkow EM. Microtubules and microtubule-associated proteins. Curr Opin Cell Biol 1995;7:72–81.
Mandelkow EM, Thies E, Trinczek B, Biernat J, Mandelkow E. MARK/PAR1 kinase is a regulator of microtubule-dependent transport in axons. J Cell Biol. 2004;167:99–110. https://doi.org/10.1083/jcb.200401085 jcb.200401085 [pii].
Manning G, Plowman GD, Hunter T, Sudarsanam S. Evolution of protein kinase signaling from yeast to man. Trends Biochem Sci 2002;27:514–520. https://doi.org/10.1016/S0968-0004(02)02179-5, [pii].
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;24:1637–1648. https://doi.org/10.1096/fj.09-148064fj 09-148064 [pii].
Matenia D, Mandelkow EM. The tau of MARK: a polarized view of the cytoskeleton. Trends Biochem Sci 2009;34:332–342. https://doi.org/10.1016/j.tibs.2009.03.008 S0968-0004(09)00102-9[pii].
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;16:4410–4422. https://doi.org/10.1091/mbc.E05-01-0081, E05-01-0081 [pii].
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;104:14336–14341. https://doi.org/10.1073/pnas.0703012104, 0703012104 [pii].
Naz F, Anjum F, Islam A, Ahmad F, Hassan MI. Microtubule affinity-regulating kinase 4: structure, function, and regulation. Cell Biochem Biophys 2013;67:485–499. https://doi.org/10.1007/s12013-013-9550-7.
Naz F, Islam A, Ahmad F, Hassan MI. Atypical PKC phosphorylates microtubule affinity-regulating kinase 4 in vitro. Mol Cell Biochem 2015a;410:223–228. https://doi.org/10.1007/s11010-015-2555-3 10.1007/s11010-015-2555-3[pii].
Naz F, Shahbaaz M, Bisetty K, Islam A, Ahmad F, Hassan MI. Designing new kinase inhibitor derivatives as therapeutics against common complex diseases: structural basis of microtubule affinity-regulating kinase 4 (MARK4) inhibition. OMICS 2015b;19:700–711. https://doi.org/10.1089/omi.2015.0111.
Naz F, Shahbaaz M, Khan S, Bisetty K, Islam A, Ahmad F, et al. PKR-inhibitor binds efficiently with human microtubule affinity-regulating kinase 4. J Mol Graph Model 2015c;62:245–252. https://doi.org/10.1016/j.jmgm.2015.10.009 S1093-3263(15)30069-3[pii].
Nigg EA, Raff JW. Centrioles, centrosomes, and cilia in health and disease. Cell 2009;139:663–678. https://doi.org/10.1016/j.cell.2009.10.036 S0092-8674(09)01362-2[pii].
Pruitt KD, Harrow J, Harte RA, Wallin C, Diekhans M, Maglott DR, et al. The consensus coding sequence (CCDS) project: identifying a common protein-coding gene set for the human and mouse genomes. Genome Res 2009;19:1316–1323. https://doi.org/10.1101/gr.080531.108 gr.080531.108[pii].
Sack JS, Gao M, Kiefer SE, Myers JE, Jr., Newitt JA, Wu S, et al. Crystal structure of microtubule affinity-regulating kinase 4 catalytic domain in complex with a pyrazolopyrimidine inhibitor. Acta Crystallogr F Struct Biol Commun 2016;72:129–134. https://doi.org/10.1107/S2053230X15024747 S2053230X15024747[pii].
Sanders MJ, Grondin PO, Hegarty BD, Snowden MA, Carling D. Investigating the mechanism for AMP activation of the AMP-activated protein kinase cascade. Biochem J. 2007;403:139–148. https://doi.org/10.1042/BJ20061520, BJ20061520 [pii].
Schmidt TI, Kleylein-Sohn J, Westendorf J, Le Clech M, Lavoie SB, Stierhof YD, et al. Control of centriole length by CPAP and CP110. Curr Biol. 2009;19:1005–1011. https://doi.org/10.1016/j.cub.2009.05.016, S0960-9822(09)01116-6 [pii].
Schmidt KN, Kuhns S, Neuner A, Hub B, Zentgraf H, Pereira G. Cep164 mediates vesicular docking to the mother centriole during early steps of ciliogenesis. J Cell Biol 2012;199:1083–1101. https://doi.org/10.1083/jcb.201202126, jcb.201202126 [pii].
Schneider A, Laage R, von Ahsen O, Fischer A, Rossner M, Scheek S, et al. Identification of regulated genes during permanent focal cerebral ischaemia: characterization of the protein kinase 9b5/MARKL1/MARK4. J Neurochem 2004;88:1114–1126. doi:2228 [pii].
Spektor A, Tsang WY, Khoo D, Dynlacht BD. Cep97 and CP110 suppress a cilia assembly program. Cell. 2007;130:678–690. https://doi.org/10.1016/j.cell.2007.06.027, S0092-8674(07)00794-5 [pii].
Stamer K, Vogel R, Thies E, Mandelkow E, Mandelkow EM. Tau blocks traffic of organelles, neurofilaments, and APP vesicles in neurons and enhances oxidative stress. J Cell Biol 2002;156:1051–1063. https://doi.org/10.1083/jcb.200108057 jcb.200108057[pii].
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;287:38305–38315. https://doi.org/10.1074/jbc.M112.388934M112.388934 [pii].
Sung CH, Leroux MR. The roles of evolutionarily conserved functional modules in cilia-related trafficking. Nat Cell Biol 2013;15:1387–1397. https://doi.org/10.1038/ncb2888 ncb2888[pii].
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;2:117–126. https://doi.org/10.4161/spmg.20724 SPMG20724[pii].
Tassan JP, Le Goff X. An overview of the KIN1/PAR-1/MARK kinase family. Biol Cell 2004;96:193–199. https://doi.org/10.1016/j.biolcel.2003.10.009 S0248490004000176[pii].
Terada S, Hirokawa N. Moving on to the cargo problem of microtubule-dependent motors in neurons. Curr Opin Neurobiol 2000;10:566–573. doi:S0959-4388(00)00129-X [pii].
Timm T, Li XY, Biernat J, Jiao J, Mandelkow E, Vandekerckhove J, et al. MARKK, a Ste20-like kinase, activates the polarity-inducing kinase MARK/PAR-1. EMBO J 2003;22:5090–5101. https://doi.org/10.1093/emboj/cdg447.
Timm T, Matenia D, Li XY, Griesshaber B, Mandelkow EM. Signaling from MARK to tau: regulation, cytoskeletal crosstalk, and pathological phosphorylation. Neurodegener Dis. 2006;3:207–217. https://doi.org/10.1159/000095258, 95258 [pii].
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 2008a;283:18873–18882. https://doi.org/10.1074/jbc.M706596200 M706596200[pii].
Timm T, Marx A, Panneerselvam S, Mandelkow E, Mandelkow EM. Structure and regulation of MARK, a kinase involved in abnormal phosphorylation of Tau protein. BMC Neurosci. 2008b;9 Suppl 2:S9. https://doi.org/10.1186/1471-2202-9-S2-S9 1471-2202-9-S2-S9[pii].
Tomancak P, Piano F, Riechmann V, Gunsalus KC, Kemphues KJ, Ephrussi A. A Drosophila melanogaster homologue of Caenorhabditis elegans par-1 acts at an early step in embryonic-axis formation. Nat Cell Biol 2000;2:458–460. https://doi.org/10.1038/35017101.
Trinczek B, Brajenovic M, Ebneth A, Drewes G. MARK4 is a novel microtubule-associated proteins/microtubule affinity-regulating kinase that binds to the cellular microtubule network and to centrosomes. J Biol Chem 2004;279:5915–5923. https://doi.org/10.1074/jbc.M304528200 M304528200[pii].
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;27:4413–4423. https://doi.org/10.1523/JNEUROSCI.0725-07.2007, 27/16/4413 [pii].
Watkins JL, Lewandowski KT, Meek SE, Storz P, Toker A, Piwnica-Worms H. Phosphorylation of the Par-1 polarity kinase by protein kinase D regulates 14-3-3 binding and membrane association. Proc Natl Acad Sci U S A 2008;105:18378–18383. https://doi.org/10.1073/pnas.0809661105 0809661105[pii].
Wodarz A, Nusse R. Mechanisms of Wnt signaling in development. Annu Rev Cell Dev Biol 1998;14:59–88. https://doi.org/10.1146/annurev.cellbio.14.1.59.
Wong EW, Sun S, Li MW, Lee WM, Cheng CY. 14-3-3 Protein regulates cell adhesion in the seminiferous epithelium of rat testes. Endocrinology 2009;150:4713–4723. https://doi.org/10.1210/en.2009-0427 en.2009-0427[pii].
Yu X, Wang Y, DeGraff DJ, Wills ML, Matusik RJ. Wnt/beta-catenin activation promotes prostate tumor progression in a mouse model. Oncogene 2011;30:1868–1879. https://doi.org/10.1038/onc.2010.560 onc2010560[pii].
Yu W, Polepalli J, Wagh D, Rajadas J, Malenka R, Lu B. A critical role for the PAR-1/MARK-tau axis in mediating the toxic effects of Abeta on synapses and dendritic spines. Hum Mol Genet 2012;21:1384–1390. https://doi.org/10.1093/hmg/ddr576 ddr576[pii].
Zhang SH, Kobayashi R, Graves PR, Piwnica-Worms H, Tonks NK. Serine phosphorylation-dependent association of the band 4.1-related protein-tyrosine phosphatase PTPH1 with 14-3-3beta protein. J Biol Chem. 1997;272:27281–27287.
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Sami, N., Kumar, V., Hassan, M.I. (2018). Microtubule Affinity Regulating Kinase-4. In: Choi, S. (eds) Encyclopedia of Signaling Molecules. Springer, Cham. https://doi.org/10.1007/978-3-319-67199-4_101744
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