Kinase Subfamily MARK

Kinase Classification: Group CAMK: Family CAMKL: Subfamily Mark

MARK (Microtubule Associated Kinases) are involved in cell polarity and cytoskeletal regulation.

Evolution

Mark kinases are found in most eukaryotes other than several parasites. The family is expanded in many clades. Vertebrates have four conserved members, MARK1-4, and many mammals have large expansions: Mouse has 24 additional MARKs, and xxx pseudogenes, of which only two have likely orthologs in rat [1], and human has 25 cataloged MARK pseudogenes [2]. A clue to this rapid evolution comes from the mouse t haplotype, a region of chromosome 17 which is preferentially transmitted to offspring. This is believed to be due to several variant loci that poison sperm that do not contain them, and a responder locus (a variant MARK called Smok-TCR) which protects sperm carrying the t haplotype [3].

Domain Structure

MARK kinases typically have an N-terminal kinase domain followed shortly by a UBA domain, a non-domain region and usually a C-terminal KA1 domain which binds acidic phospholipids and may help anchor to the plasma membrane [4].

Functions

MARK kinases have roles in cytoskeletal organization and cell polarity in many organisms. In both C. elegans and Drosophila, MARK kinases are localized to the posterior of the early embryo and oocytes, respectively, opposite to the localization of the aPKC complex, and help control polarized cell division. In both Drosophila and mammalian cells, MARK kinases are localized basally, while aPKC is localized apically. MARK kinases are also involved in neuronal polarity [5], regulation of microtubule polymerization [6] in Wnt [7] and Hippo [8] signaling and in mammalian metabolism [9].

References

1. Caenepeel S, Charydczak G, Sudarsanam S, Hunter T, and Manning G. The mouse kinome: discovery and comparative genomics of all mouse protein kinases. Proc Natl Acad Sci U S A. 2004 Aug 10;101(32):11707-12. DOI:10.1073/pnas.0306880101 |
2. Manning G, Whyte DB, Martinez R, Hunter T, and Sudarsanam S. The protein kinase complement of the human genome. Science. 2002 Dec 6;298(5600):1912-34. DOI:10.1126/science.1075762 |
3. Herrmann BG, Koschorz B, Wertz K, McLaughlin KJ, and Kispert A. A protein kinase encoded by the t complex responder gene causes non-mendelian inheritance. Nature. 1999 Nov 11;402(6758):141-6. DOI:10.1038/45970 |
4. Moravcevic K, Mendrola JM, Schmitz KR, Wang YH, Slochower D, Janmey PA, and Lemmon MA. Kinase associated-1 domains drive MARK/PAR1 kinases to membrane targets by binding acidic phospholipids. Cell. 2010 Dec 10;143(6):966-77. DOI:10.1016/j.cell.2010.11.028 |
5. Reiner O and 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 |
6. Hayashi K, Suzuki A, and Ohno S. PAR-1/MARK: a kinase essential for maintaining the dynamic state of microtubules. Cell Struct Funct. 2012;37(1):21-5. DOI:10.1247/csf.11038 |
7. Sun TQ, Lu B, Feng JJ, Reinhard C, Jan YN, Fantl WJ, and Williams LT. PAR-1 is a Dishevelled-associated kinase and a positive regulator of Wnt signalling. Nat Cell Biol. 2001 Jul;3(7):628-36. DOI:10.1038/35083016 |
8. Mohseni M, Sun J, Lau A, Curtis S, Goldsmith J, Fox VL, Wei C, Frazier M, Samson O, Wong KK, Kim C, and Camargo FD. A genetic screen identifies an LKB1-MARK signalling axis controlling the Hippo-YAP pathway. Nat Cell Biol. 2014 Jan;16(1):108-17. DOI:10.1038/ncb2884 |
9. Hurov J and Piwnica-Worms H. The Par-1/MARK family of protein kinases: from polarity to metabolism. Cell Cycle. 2007 Aug 15;6(16):1966-9. DOI:10.4161/cc.6.16.4576 |