Orphan Kinases Turn Eccentric: a New Class of Cyclin Y-activated, Membrane-targeted CDKs

Overview

Journal Cell Cycle

Specialty Cell Biology

Date 2012 Aug 17

PMID 22895054

Citations 32

Authors

Petra Mikolcevic

Johannes Rainer

Stephan Geley

Affiliations

Soon will be listed here.

Abstract

PCTAIRE kinases (PCTK) are a highly conserved, but poorly characterized, subgroup of cyclin-dependent kinases (CDK). They are characterized by a conserved catalytic domain flanked by N- and C-terminal extensions that are involved in cyclin binding. Vertebrate genomes contain three highly similar PCTAIRE kinases (PCTK1,2,3, a.k.a., CDK16,17,18), which are most abundant in post-mitotic cells in brain and testis. Consistent with this restricted expression pattern, PCTK1 (CDK16) has recently been shown to be essential for spermatogenesis. PCTAIREs are activated by cyclin Y (CCNY), a highly conserved single cyclin fold protein. By binding to N-myristoylated CCNY, CDK16 is targeted to the plasma membrane. Unlike conventional cyclin-CDK interactions, binding of CCNY to CDK16 not only requires the catalytic domain, but also domains within the N-terminal extension. Interestingly, phosphorylation within this domain blocks CCNY binding, providing a novel means of cyclin-CDK regulation. By using these functional characteristics, we analyzed "PCTAIRE" sequence containing protein kinase genes in genomes of various organisms and found that CCNY and CCNY-dependent kinases are restricted to eumetazoa and possibly evolved along with development of a central nervous system. Here, we focus on the structure and regulation of PCTAIREs and discuss their established functions.

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References

Manning G, Whyte D, Martinez R, Hunter T, Sudarsanam S . The protein kinase complement of the human genome. Science. 2002; 298(5600):1912-34. DOI: 10.1126/science.1075762. View

Hemerly A, Ferreira P, Van Montagu M, Engler G, Inze D . Cell division events are essential for embryo patterning and morphogenesis: studies on dominant-negative cdc2aAt mutants of arabidopsis. Plant J. 2000; 23(1):123-30. DOI: 10.1046/j.1365-313x.2000.00800.x. View

Gibson T, Thompson J, Blocker A, Kouzarides T . Evidence for a protein domain superfamily shared by the cyclins, TFIIB and RB/p107. Nucleic Acids Res. 1994; 22(6):946-52. PMC: 307913. DOI: 10.1093/nar/22.6.946. View

Petri E, Errico A, Escobedo L, Hunt T, Basavappa R . The crystal structure of human cyclin B. Cell Cycle. 2007; 6(11):1342-9. DOI: 10.4161/cc.6.11.4297. View

Matsuoka M, Matsuura Y, Semba K, Nishimoto I . Molecular cloning of a cyclin-like protein associated with cyclin-dependent kinase 3 (cdk 3) in vivo. Biochem Biophys Res Commun. 2000; 273(2):442-7. DOI: 10.1006/bbrc.2000.2965. View

Schierwater B, de Jong D, DeSalle R . Placozoa and the evolution of Metazoa and intrasomatic cell differentiation. Int J Biochem Cell Biol. 2008; 41(2):370-9. DOI: 10.1016/j.biocel.2008.09.023. View

Carroll A, OShea E . Pho85 and signaling environmental conditions. Trends Biochem Sci. 2002; 27(2):87-93. DOI: 10.1016/s0968-0004(01)02040-0. View

Miller D, Ball E . Animal evolution: the enigmatic phylum placozoa revisited. Curr Biol. 2005; 15(1):R26-8. DOI: 10.1016/j.cub.2004.12.016. View

Michaelis C, Weeks G . The isolation from a unicellular organism, Dictyostelium discoideum, of a highly-related cdc2 gene with characteristics of the PCTAIRE subfamily. Biochim Biophys Acta. 1993; 1179(2):117-24. DOI: 10.1016/0167-4889(93)90132-9. View

10.

Hirose T, Tamaru T, Okumura N, Nagai K, Okada M . PCTAIRE 2, a Cdc2-related serine/threonine kinase, is predominantly expressed in terminally differentiated neurons. Eur J Biochem. 1997; 249(2):481-8. DOI: 10.1111/j.1432-1033.1997.t01-1-00481.x. View

11.

Rhee K, Wolgemuth D . Cdk family genes are expressed not only in dividing but also in terminally differentiated mouse germ cells, suggesting their possible function during both cell division and differentiation. Dev Dyn. 1995; 204(4):406-20. DOI: 10.1002/aja.1002040407. View

12.

Henikoff S, Henikoff J . Amino acid substitution matrices from protein blocks. Proc Natl Acad Sci U S A. 1992; 89(22):10915-9. PMC: 50453. DOI: 10.1073/pnas.89.22.10915. View

13.

Liu Y, Cheng K, Gong K, Fu A, Ip N . Pctaire1 phosphorylates N-ethylmaleimide-sensitive fusion protein: implications in the regulation of its hexamerization and exocytosis. J Biol Chem. 2006; 281(15):9852-8. DOI: 10.1074/jbc.M513496200. View

14.

Stowers R, Garza D, Rascle A, Hogness D . The L63 gene is necessary for the ecdysone-induced 63E late puff and encodes CDK proteins required for Drosophila development. Dev Biol. 2000; 221(1):23-40. DOI: 10.1006/dbio.2000.9685. View

15.

Andersen G, Busso D, Poterszman A, Hwang J, Wurtz J, Ripp R . The structure of cyclin H: common mode of kinase activation and specific features. EMBO J. 1997; 16(5):958-67. PMC: 1169696. DOI: 10.1093/emboj/16.5.958. View

16.

Insall R . The Dictyostelium genome: the private life of a social model revealed?. Genome Biol. 2005; 6(6):222. PMC: 1175964. DOI: 10.1186/gb-2005-6-6-222. View

17.

Jeffrey P, Russo A, Polyak K, Gibbs E, Hurwitz J, Massague J . Mechanism of CDK activation revealed by the structure of a cyclinA-CDK2 complex. Nature. 1995; 376(6538):313-20. DOI: 10.1038/376313a0. View

18.

Eloy N, Coppens F, Beemster G, Hemerly A, Ferreira P . The Arabidopsis anaphase promoting complex (APC): regulation through subunit availability in plant tissues. Cell Cycle. 2006; 5(17):1957-65. DOI: 10.4161/cc.5.17.3125. View

19.

Eisenmann D . Wnt signaling. WormBook. 2007; :1-17. PMC: 4781570. DOI: 10.1895/wormbook.1.7.1. View

20.

Tang X, Guilherme A, Chakladar A, Powelka A, Konda S, Virbasius J . An RNA interference-based screen identifies MAP4K4/NIK as a negative regulator of PPARgamma, adipogenesis, and insulin-responsive hexose transport. Proc Natl Acad Sci U S A. 2006; 103(7):2087-92. PMC: 1413698. DOI: 10.1073/pnas.0507660103. View