Kinase Subfamily MAK

From WikiKinome

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) Fu, or by CAK1 (CDK-activating kinase) but not by human CDK7, MEK1 or MEK5Fu2. 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 Garrido

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 Bladt. 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 Omori. 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 Shinkai 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 Fu3. 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 Lahiry. 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 Fu2. Despite its name ICK is expressed in many tissues, and

Loss of function mutants of MAK in Chlamydomonas Berman, C. elegans , and Leishmania Bengs 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 Chen. It is expressed in several sets of ciliated chemosensory neurons and male-specific cells, and required for normal chemotaxis, dauer formation, and male mating Starich. dyf-5 may be involved in docking and undocking of cargo from two distinct kinesin motors within the cilium Burghoon.

Yeast IME2 is involved in meiosis and pseudohyphal growth Strudwick. Schizosaccharomyces pombe has two MAK genes, Mde3 and Pit1, which interact genetically and are regulated by the meiosis-specific transcription factor, Mei4Abe; mutants have minor defects in sporulation. Other fungal MAK genes have roles in mating and fruiting body formation (reviewed in Irniger).

References

<biblio>

1. Abe pmid=10747048
2. Bengs pmid=15720564
3. Berman pmid=12842015
4. Burghoorn pmid=17420466
5. Bladt pmid=8359591
6. Chen pmid=17187676
7. Fu pmid=16954377
8. Fu2 pmid=15988018
9. Fu3 pmid=19696144
10. Irniger pmid=21306447
11. Lahiry pmid=19185282
12. Ma pmid=16951154
13. Omori pmid=21148103
14. Shinkai pmid=11971961
15. Starich pmid=7705621
16. Xia pmid=12084720

</biblio>

Broken References (temporary)

<biblio>

1. Garrido pmid=15601825
2. Strudwick pmid=20876298

</biblio>