title: Regulation of CK2 by phosphorylation and O-GlcNAcylation revealed by semisynthesis.
abstract: Protein serine-threonine kinase casein kinase II (CK2) is involved in a myriad of cellular processes including cell growth and proliferation through its phosphorylation of hundreds of substrates, yet how CK2 function is regulated is poorly understood. Here we report that the CK2 catalytic subunit CK2α is modified by O-linked β-N-acetyl-glucosamine (O-GlcNAc) on Ser347, proximal to a cyclin-dependent kinase phosphorylation site (Thr344). We use protein semisynthesis to show that phosphorylation of Thr344 increases the cellular stability of CK2α by strengthening its interaction with Pin1, whereas glycosylation of Ser347 seems to be antagonistic to Thr344 phosphorylation and permissive to proteasomal degradation. By performing kinase assays with site-specifically phospho- and glyco-modified CK2α in combination with CK2β and Pin1 binding partners on human protein microarrays, we show that the kinase substrate selectivity of CK2 is modulated by these specific post-translational modifications. This study suggests how a promiscuous protein kinase can be regulated at multiple levels to achieve particular biological outputs.
authors.affiliation: Department of Pharmacology and Molecular Sciences, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Mary Katherine
authors.initials: MK
authors.lastname: Tarrant
authors.forename: Hee-Sool
authors.initials: HS
authors.lastname: Rho
authors.forename: Zhi
authors.initials: Z
authors.lastname: Xie
authors.forename: Yu Lin
authors.initials: YL
authors.lastname: Jiang
authors.forename: Christopher
authors.initials: C
authors.lastname: Gross
authors.forename: Jeffrey C
authors.initials: JC
authors.lastname: Culhane
authors.forename: Gai
authors.initials: G
authors.lastname: Yan
authors.forename: Jiang
authors.initials: J
authors.lastname: Qian
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Ichikawa
authors.forename: Tatsuji
authors.initials: T
authors.lastname: Matsuoka
authors.forename: Natasha
authors.initials: N
authors.lastname: Zachara
authors.forename: Felicia A
authors.initials: FA
authors.lastname: Etzkorn
authors.forename: Gerald W
authors.initials: GW
authors.lastname: Hart
authors.forename: Jun Seop
authors.initials: JS
authors.lastname: Jeong
authors.forename: Seth
authors.initials: S
authors.lastname: Blackshaw
authors.forename: Heng
authors.initials: H
authors.lastname: Zhu
authors.forename: Philip A
authors.initials: PA
authors.lastname: Cole
mesh_terms: D000117:Acetylglucosamine / Q000378:metabolism*; D000818:Animals; D047390:Casein Kinase II / Q000096:biosynthesis / Q000737:chemistry / Q000378:metabolism*; D002460:Cell Line; D006801:Humans; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D019696:Peptidylprolyl Isomerase / Q000737:chemistry / Q000378:metabolism; D010766:Phosphorylation; D051381:Rats; D012694:Serine / Q000378:metabolism
chemical_list: D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D012694:Serine; D047390:Casein Kinase II; C000606846:PIN1 protein, human; D019696:Peptidylprolyl Isomerase; D000117:Acetylglucosamine