title: Dephosphorylation at a conserved SP motif governs cAMP sensitivity and nuclear localization of class IIa histone deacetylases.
abstract: Histone deacetylase 4 (HDAC4) and its paralogs, HDAC5, -7, and -9 (all members of class IIa), possess multiple phosphorylation sites crucial for 14-3-3 binding and subsequent nuclear export. cAMP signaling stimulates nuclear import of HDAC4 and HDAC5, but the underlying mechanisms remain to be elucidated. Here we show that cAMP potentiates nuclear localization of HDAC9. Mutation of an SP motif conserved in HDAC4, -5, and -9 prevents cAMP-stimulated nuclear localization. Unexpectedly, this treatment inhibits phosphorylation at the SP motif, indicating an inverse relationship between the phosphorylation event and nuclear import. Consistent with this, leptomycin B-induced nuclear import and adrenocorticotropic hormone (ACTH) treatment result in the dephosphorylation at the motif. Moreover, the modification synergizes with phosphorylation at a nearby site, and similar kinetics was observed for both phosphorylation events during myoblast and adipocyte differentiation. These results thus unravel a previously unrecognized mechanism whereby cAMP promotes dephosphorylation and differentially regulates multisite phosphorylation and the nuclear localization of class IIa HDACs.
authors.affiliation: Rosalind and Morris Goodman Cancer Research Center, McGill University, Montréal, Québec H3A 1A3, Canada.
authors.forename: Donald R
authors.initials: DR
authors.lastname: Walkinshaw
authors.forename: Ryan
authors.initials: R
authors.lastname: Weist
authors.forename: Lin
authors.initials: L
authors.lastname: Xiao
authors.forename: Kezhi
authors.initials: K
authors.lastname: Yan
authors.forename: Go-Woon
authors.initials: GW
authors.lastname: Kim
authors.forename: Xiang-Jiao
authors.initials: XJ
authors.lastname: Yang
mesh_terms: D016475:3T3 Cells; D021581:Active Transport, Cell Nucleus; D020816:Amino Acid Motifs; D000818:Animals; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D057809:HEK293 Cells; D006367:HeLa Cells; D006655:Histone Deacetylases / Q000096:biosynthesis* / Q000737:chemistry; D006801:Humans; D007313:Insecta; D051379:Mice; D010766:Phosphorylation; D010957:Plasmids / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D006655:Histone Deacetylases