title: Cyclin-dependent kinase 16/PCTAIRE kinase 1 is activated by cyclin Y and is essential for spermatogenesis.
abstract: Cyclin-dependent kinase 16 (CDK16, PCTK1) is a poorly characterized protein kinase, highly expressed in the testis and the brain. Here, we report that CDK16 is activated by membrane-associated cyclin Y (CCNY). Treatment of transfected human cells with the protein kinase A (PKA) activator forskolin blocked, while kinase inhibition promoted, CCNY-dependent targeting of CDK16-green fluorescent protein (GFP) to the cell membrane. CCNY binding to CDK16 required a region upstream of the kinase domain and was found to be inhibited by phosphorylation of serine 153, a potential PKA phosphorylation site. Thus, in contrast to other CDKs, CDK16 is regulated by phosphorylation-controlled cyclin binding. CDK16 isolated from murine testis was unphosphorylated, interacted with CCNY, and exhibited kinase activity. To investigate the function of CDK16 in vivo, we established a conditional knockout allele. Mice lacking CDK16 developed normally, but male mice were infertile. Spermatozoa isolated from their epididymis displayed thinning and elongation of the annulus region, adopted a bent shape, and showed impaired motility. Moreover, CDK16-deficient spermatozoa had malformed heads and excess residual cytoplasm, suggesting a role of CDK16 in spermiation. Thus, CDK16 is a membrane-targeted CDK essential for spermatogenesis.
authors.affiliation: Division of Molecular Pathophysiology, Biocenter, Innsbruck Medical University, Innsbruck, Austria.
authors.forename: Petra
authors.initials: P
authors.lastname: Mikolcevic
authors.forename: Reinhard
authors.initials: R
authors.lastname: Sigl
authors.forename: Veronika
authors.initials: V
authors.lastname: Rauch
authors.forename: Michael W
authors.initials: MW
authors.lastname: Hess
authors.forename: Kristian
authors.initials: K
authors.lastname: Pfaller
authors.forename: Marin
authors.initials: M
authors.lastname: Barisic
authors.forename: Lauri J
authors.initials: LJ
authors.lastname: Pelliniemi
authors.forename: Michael
authors.initials: M
authors.lastname: Boesl
authors.forename: Stephan
authors.initials: S
authors.lastname: Geley
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D018844:Cyclin-Dependent Kinases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D016213:Cyclins / Q000235:genetics / Q000378:metabolism*; D017931:DNA Primers / Q000235:genetics; D004789:Enzyme Activation; D005260:Female; D006801:Humans; D007248:Infertility, Male / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D010766:Phosphorylation; D011485:Protein Binding; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D013091:Spermatogenesis / Q000235:genetics / Q000502:physiology*; D013094:Spermatozoa / Q000002:abnormalities
chemical_list: C543319:CCNY protein, human; D016213:Cyclins; D017931:DNA Primers; D011994:Recombinant Proteins; D018844:Cyclin-Dependent Kinases; C089463:PCTAIRE-1 protein kinase