title: Phosphatases Generate Signal Specificity Downstream of Ssp1 Kinase in Fission Yeast.
abstract: AMPK-related protein kinases (ARKs) coordinate cell growth, proliferation, and migration with environmental status. It is unclear how specific ARKs are activated at specific times. In the fission yeastSchizosaccharomyces pombe, the CaMKK-like protein kinase Ssp1 promotes cell cycle progression by activating the ARK Cdr2 according to cell growth signals. Here, we demonstrate that Ssp1 activates a second ARK, Ssp2/AMPKα, for cell proliferation in low environmental glucose. Ssp1 activates these two related targets by the same biochemical mechanism: direct phosphorylation of a conserved residue in the activation loop (Cdr2-T166 and Ssp2-T189). Despite a shared upstream kinase and similar phosphorylation sites, Cdr2 and Ssp2 have distinct regulatory input cues and distinct functional outputs. We investigated this specificity and found that distinct protein phosphatases counteract Ssp1 activity toward its different substrates. We identified the PP6 family phosphatase Ppe1 as the primary phosphatase for Ssp2-T189 dephosphorylation. The phosphatase inhibitor Sds23 acts upstream of PP6 to regulate Ssp2-T189 phosphorylation in a manner that depends on energy but not on the intact AMPK heterotrimer. In contrast, Cdr2-T166 phosphorylation is regulated by protein phosphatase 2A but not by the Sds23-PP6 pathway. Thus, our study provides a phosphatase-driven mechanism to induce specific physiological responses downstream of a master protein kinase.
authors.affiliation: Department of Biochemistry and Cell Biology, The Geisel School of Medicine at Dartmouth, Hanover, New Hampshire, USA.
authors.forename: Lin
authors.initials: L
authors.lastname: Deng
authors.affiliation: Department of Biochemistry and Cell Biology, The Geisel School of Medicine at Dartmouth, Hanover, New Hampshire, USA.
authors.forename: Mid Eum
authors.initials: ME
authors.lastname: Lee
authors.affiliation: Department of Biochemistry and Cell Biology, The Geisel School of Medicine at Dartmouth, Hanover, New Hampshire, USA.
authors.forename: Katherine L
authors.initials: KL
authors.lastname: Schutt
authors.affiliation: Department of Biochemistry and Cell Biology, The Geisel School of Medicine at Dartmouth, Hanover, New Hampshire, USA james.b.moseley@dartmouth.edu.
authors.forename: James B
authors.initials: JB
authors.lastname: Moseley
mesh_terms: D002453:Cell Cycle / Q000502:physiology*; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism*; D010749:Phosphoprotein Phosphatases / Q000378:metabolism*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D012568:Schizosaccharomyces / Q000254:growth & development / Q000378:metabolism*; D029702:Schizosaccharomyces pombe Proteins / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D018840:HSP70 Heat-Shock Proteins; C111935:PSS1 protein, S pombe; D029702:Schizosaccharomyces pombe Proteins; C542567:Cdr2 protein, S pombe; D017346:Protein Serine-Threonine Kinases; C573920:Ssp2 protein, S pombe; D010749:Phosphoprotein Phosphatases
keywords: AMPK; Cdr2; Ssp1; fission yeast; kinase; phosphatase; pombe