Kinase Subfamily MAK

Kinase Classification: Group CMGC: Family RCK: MAK

Evolution

MAK is found in all eukaryotes examined to date. Vertebrates have two copies: MAK and ICK, while most invertebrates have one copy.

Domain Structure

All MAK kinases have an N-terminal kinase domain and a variable length (~100-300 AA) C-terminal tail without any known domains.

Activation

Most MAK kinases have a T[DE]Y motif in their activation loop. In ICK, the Y159 is autophosphorylated, and required for basal activity, while the T is transphosphorylated. In vitro, ICK can be threonine-phosphorylated by CDK20 (CCRK) [1], or by CAK1 (CDK-activating kinase) but not by human CDK7, MEK1 or MEK5[2]. Protein phosphatase 5 (PP5) binds to and can dephosphorylate ICK on T157. Thus the activation loop looks like MAPK in terms of the TxY, but possibly like a CDK in terms of CAK1 activation. By contrast, a MAK from the fungus Ustilago maydis is apparently activated by a MEK1 kinase [3]

Function

Human MAK (Male germ-cell Associated Kinase) is expressed almost exclusively in germ cells of the testis. In rodents, it associates with the synaptonemal complex (paired chromosomes) during meiosis. Mouse MAK is also expressed in developing sensory epithelia, including photoreceptors, olfactory receptors and the respiratory tract [4]. In the retina, MAK is found in the connecting cilia and outer-segment axonemes of photoreceptor cells and loss of MAK results in longer cilia [5]. BioGPS data show human and mouse MAK highly restricted to retina, pineal gland, testis, olfactory epithelium and possibly lung in adult tissues, while ICK is more broadly expressed, though elevated in lung, retina and intestine. Antibody staining (proteinatlas.org) shows ICK in cytoplasmic vesicles (possibly golgi or mitochondria) and in tissues, found in gastro-intestinal tract, nasopharynx and cervix. MAK was found weakly in the cytoplasm and also in the nucleus, with strongest staining in stomach and Purkinje cells.

MAK knockout mice [6] have no major abnormalities, though they have slightly reduced litter sizes and sperm motility.

Knockdown of ICK in intestinal epithelial cells inhibited cell cycle progress, and also protein translation, though a likely binding and phosphorylation of the mTOR-Raptor complex [7]. A hypomorphic mutation in ICK causes endocrine-cerebro-osteodysplasia (ECO), a neonatal-lethal disease with multiple disorders in skeletal, cerebral, genital, pituitary and endocrine development [8]. The phenotypes are similar to those of Majewski syndrome, which may be caused by the NEK1 kinase.

ICK has two splice forms, of which the longer is cytoplasmic and the shorter is nuclear [2]. Despite its name ICK is expressed in many tissues, and

Loss of function mutants of MAK in Chlamydomonas [9], C. elegans [], and Leishmania [10] result in abnormally long cilia, while overexpression leads to truncated cilia.

C. elegans dyf-5 (M04C9.5) is well-characterized for its role in regulating flagellar length, and the localization of several other proteins in the flagellum (cilium). Dyf-5 is expressed under the control of the flagellar transcription factor, DAF-19 [11]. It is expressed in several sets of ciliated chemosensory neurons and male-specific cells, and required for normal chemotaxis, dauer formation, and male mating [12]. dyf-5 may be involved in docking and undocking of cargo from two distinct kinesin motors within the cilium [13].

Yeast IME2 is involved in meiosis and pseudohyphal growth [14]. Schizosaccharomyces pombe has two MAK genes, Mde3 and Pit1, which interact genetically and are regulated by the meiosis-specific transcription factor, Mei4[15]; mutants have minor defects in sporulation. Other fungal MAK genes have roles in mating and fruiting body formation (reviewed in [16]).

References

1. Fu Z, Larson KA, Chitta RK, Parker SA, Turk BE, Lawrence MW, Kaldis P, Galaktionov K, Cohn SM, Shabanowitz J, Hunt DF, and Sturgill TW. Identification of yin-yang regulators and a phosphorylation consensus for male germ cell-associated kinase (MAK)-related kinase. Mol Cell Biol. 2006 Nov;26(22):8639-54. DOI:10.1128/MCB.00816-06 |
2. Fu Z, Schroeder MJ, Shabanowitz J, Kaldis P, Togawa K, Rustgi AK, Hunt DF, and Sturgill TW. Activation of a nuclear Cdc2-related kinase within a mitogen-activated protein kinase-like TDY motif by autophosphorylation and cyclin-dependent protein kinase-activating kinase. Mol Cell Biol. 2005 Jul;25(14):6047-64. DOI:10.1128/MCB.25.14.6047-6064.2005 |
3. Garrido E, Voss U, Müller P, Castillo-Lluva S, Kahmann R, and Pérez-Martín J. The induction of sexual development and virulence in the smut fungus Ustilago maydis depends on Crk1, a novel MAPK protein. Genes Dev. 2004 Dec 15;18(24):3117-30. DOI:10.1101/gad.314904 |
4. Bladt F and Birchmeier C. Characterization and expression analysis of the murine rck gene: a protein kinase with a potential function in sensory cells. Differentiation. 1993 Jun;53(2):115-22. DOI:10.1111/j.1432-0436.1993.tb00651.x |
5. Omori Y, Chaya T, Katoh K, Kajimura N, Sato S, Muraoka K, Ueno S, Koyasu T, Kondo M, and Furukawa T. Negative regulation of ciliary length by ciliary male germ cell-associated kinase (Mak) is required for retinal photoreceptor survival. Proc Natl Acad Sci U S A. 2010 Dec 28;107(52):22671-6. DOI:10.1073/pnas.1009437108 |
6. Shinkai Y, Satoh H, Takeda N, Fukuda M, Chiba E, Kato T, Kuramochi T, and Araki Y. A testicular germ cell-associated serine-threonine kinase, MAK, is dispensable for sperm formation. Mol Cell Biol. 2002 May;22(10):3276-80. DOI:10.1128/MCB.22.10.3276-3280.2002 |
7. Fu Z, Kim J, Vidrich A, Sturgill TW, and Cohn SM. Intestinal cell kinase, a MAP kinase-related kinase, regulates proliferation and G1 cell cycle progression of intestinal epithelial cells. Am J Physiol Gastrointest Liver Physiol. 2009 Oct;297(4):G632-40. DOI:10.1152/ajpgi.00066.2009 |
8. Lahiry P, Wang J, Robinson JF, Turowec JP, Litchfield DW, Lanktree MB, Gloor GB, Puffenberger EG, Strauss KA, Martens MB, Ramsay DA, Rupar CA, Siu V, and Hegele RA. A multiplex human syndrome implicates a key role for intestinal cell kinase in development of central nervous, skeletal, and endocrine systems. Am J Hum Genet. 2009 Feb;84(2):134-47. DOI:10.1016/j.ajhg.2008.12.017 |
9. Berman SA, Wilson NF, Haas NA, and Lefebvre PA. A novel MAP kinase regulates flagellar length in Chlamydomonas. Curr Biol. 2003 Jul 1;13(13):1145-9. DOI:10.1016/s0960-9822(03)00415-9 |
10. Bengs F, Scholz A, Kuhn D, and Wiese M. LmxMPK9, a mitogen-activated protein kinase homologue affects flagellar length in Leishmania mexicana. Mol Microbiol. 2005 Mar;55(5):1606-15. DOI:10.1111/j.1365-2958.2005.04498.x |
11. Chen N, Mah A, Blacque OE, Chu J, Phgora K, Bakhoum MW, Newbury CR, Khattra J, Chan S, Go A, Efimenko E, Johnsen R, Phirke P, Swoboda P, Marra M, Moerman DG, Leroux MR, Baillie DL, and Stein LD. Identification of ciliary and ciliopathy genes in Caenorhabditis elegans through comparative genomics. Genome Biol. 2006;7(12):R126. DOI:10.1186/gb-2006-7-12-r126 |
12. Starich TA, Herman RK, Kari CK, Yeh WH, Schackwitz WS, Schuyler MW, Collet J, Thomas JH, and Riddle DL. Mutations affecting the chemosensory neurons of Caenorhabditis elegans. Genetics. 1995 Jan;139(1):171-88. DOI:10.1093/genetics/139.1.171 |
14. Strudwick N, Brown M, Parmar VM, and Schröder M. Ime1 and Ime2 are required for pseudohyphal growth of Saccharomyces cerevisiae on nonfermentable carbon sources. Mol Cell Biol. 2010 Dec;30(23):5514-30. DOI:10.1128/MCB.00390-10 |
15. Abe H and Shimoda C. Autoregulated expression of Schizosaccharomyces pombe meiosis-specific transcription factor Mei4 and a genome-wide search for its target genes. Genetics. 2000 Apr;154(4):1497-508. DOI:10.1093/genetics/154.4.1497 |
16. Irniger S. The Ime2 protein kinase family in fungi: more duties than just meiosis. Mol Microbiol. 2011 Apr;80(1):1-13. DOI:10.1111/j.1365-2958.2011.07575.x |
17. Burghoorn J, Dekkers MP, Rademakers S, de Jong T, Willemsen R, and Jansen G. Mutation of the MAP kinase DYF-5 affects docking and undocking of kinesin-2 motors and reduces their speed in the cilia of Caenorhabditis elegans. Proc Natl Acad Sci U S A. 2007 Apr 24;104(17):7157-62. DOI:10.1073/pnas.0606974104 |
18. Ma AH, Xia L, Desai SJ, Boucher DL, Guan Y, Shih HM, Shi XB, deVere White RW, Chen HW, Tepper CG, and Kung HJ. Male germ cell-associated kinase, a male-specific kinase regulated by androgen, is a coactivator of androgen receptor in prostate cancer cells. Cancer Res. 2006 Sep 1;66(17):8439-47. DOI:10.1158/0008-5472.CAN-06-1636 |
19. Xia L, Robinson D, Ma AH, Chen HC, Wu F, Qiu Y, and Kung HJ. Identification of human male germ cell-associated kinase, a kinase transcriptionally activated by androgen in prostate cancer cells. J Biol Chem. 2002 Sep 20;277(38):35422-33. DOI:10.1074/jbc.M203940200 |