title: Regulation of ribosomal protein S6 phosphorylation by casein kinase 1 and protein phosphatase 1.
abstract: Ribosomal protein S6 (rpS6) is a critical component of the 40 S ribosomal subunit that mediates translation initiation at the 5'-m(7)GpppG cap of mRNA. In response to mitogenic stimuli, rpS6 undergoes ordered C-terminal phosphorylation by p70 S6 kinases and p90 ribosomal S6 kinases on four conserved Ser residues (Ser-235, Ser-236, Ser-240, and Ser-244) whose modification potentiates rpS6 cap binding activity. A fifth site, Ser-247, is also known to be phosphorylated, but its function and regulation are not well characterized. In this study, we employed phospho-specific antibodies to show that Ser-247 is a target of the casein kinase 1 (CK1) family of protein kinases. CK1-dependent phosphorylation of Ser-247 was induced by mitogenic stimuli and required prior phosphorylation of upstream S6 kinase/ribosomal S6 kinase residues. CK1-mediated phosphorylation of Ser-247 also enhanced the phosphorylation of upstream sites, which implies that bidirectional synergy between C-terminal phospho-residues is required to sustain rpS6 phosphorylation. Consistent with this idea, CK1-dependent phosphorylation of rpS6 promotes its association with the mRNA cap-binding complex in vitro. Additionally, we show that protein phosphatase 1 (PP1) antagonizes rpS6 C terminus phosphorylation and cap binding in intact cells. These findings further our understanding of rpS6 phospho-regulation and define a direct link between CK1 and translation initiation.
authors.affiliation: From the Department of Pharmacology,; Molecular and Environmental Toxicology Center, and.
authors.forename: John A
authors.initials: JA
authors.lastname: Hutchinson
authors.affiliation: From the Department of Pharmacology,; Molecular and Cellular Pharmacology Program, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin 53706.
authors.forename: Naval P
authors.initials: NP
authors.lastname: Shanware
authors.affiliation: From the Department of Pharmacology.
authors.forename: Haeyoon
authors.initials: H
authors.lastname: Chang
authors.affiliation: From the Department of Pharmacology,; Molecular and Environmental Toxicology Center, and; Molecular and Cellular Pharmacology Program, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin 53706. Electronic address: rstibbetts@wisc.edu.
authors.forename: Randal S
authors.initials: RS
authors.lastname: Tibbetts
mesh_terms: D047389:Casein Kinase I / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D010442:Peptide Chain Initiation, Translational / Q000502:physiology*; D010766:Phosphorylation / Q000502:physiology; D054645:Protein Phosphatase 1 / Q000235:genetics / Q000378:metabolism*; D012315:RNA Caps / Q000235:genetics / Q000378:metabolism*; D038601:Ribosomal Protein S6 / Q000235:genetics / Q000378:metabolism*; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000235:genetics / Q000378:metabolism
chemical_list: D012315:RNA Caps; D038601:Ribosomal Protein S6; D047389:Casein Kinase I; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D054645:Protein Phosphatase 1