title: The tumor suppressor kinase LKB1 activates the downstream kinases SIK2 and SIK3 to stimulate nuclear export of class IIa histone deacetylases.
abstract: Histone deacetylases 4 (HDAC4), -5, -7, and -9 form class IIa within the HDAC superfamily and regulate diverse physiological and pathological cellular programs. With conserved motifs for phosphorylation-dependent 14-3-3 binding, these deacetylases serve as novel signal transducers that are able to modulate histone acetylation and gene expression in response to extracellular cues. Here, we report that in a PKA-sensitive manner the tumor suppressor kinase LKB1 acts through salt-inducible kinase 2 (SIK2) and SIK3 to promote nucleocytoplasmic trafficking of class IIa HDACs. Both SIK2 and SIK3 phosphorylate the deacetylases at the conserved motifs and stimulate 14-3-3 binding. SIK2 activates MEF2-dependent transcription and relieves repression of myogenesis by the deacetylases. Distinct from SIK2, SIK3 induces nuclear export of the deacetylases independent of kinase activity and 14-3-3 binding. These findings highlight the difference among members of the SIK family and indicate that LKB1-dependent SIK activation constitutes an important signaling module upstream from class IIa deacetylases for regulating cellular programs controlled by MEF2 and other transcription factors.
authors: Rosalind and Morris Goodman Cancer Research Center, McGill University, Montréal, Québec H3A 1A3, Canada.
authors: Donald R
authors: DR
authors: Walkinshaw
authors: Ryan
authors: R
authors: Weist
authors: Go-Woon
authors: GW
authors: Kim
authors: Linya
authors: L
authors: You
authors: Lin
authors: L
authors: Xiao
authors: Jianyun
authors: J
authors: Nie
authors: Cathy S
authors: CS
authors: Li
authors: Songping
authors: S
authors: Zhao
authors: Minghong
authors: M
authors: Xu
authors: Xiang-Jiao
authors: XJ
authors: Yang
mesh_terms: D048948:14-3-3 Proteins / Q000378:metabolism; D000091162:AMP-Activated Protein Kinase Kinases; D055372:AMP-Activated Protein Kinases; D000818:Animals; D045744:Cell Line, Tumor; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D017930:Genes, Reporter; D057809:HEK293 Cells; D006367:HeLa Cells; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D051379:Mice; D011485:Protein Binding; D011494:Protein Kinases / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D048948:14-3-3 Proteins; D011494:Protein Kinases; C551842:salt-inducible kinase-2, human; C474808:salt-inducible kinase-2, mouse; D017346:Protein Serine-Threonine Kinases; C509079:SIK3 protein, human; C571369:SIK3 protein, mouse; C109790:STK11 protein, human; C491654:Stk11 protein, mouse; D017868:Cyclic AMP-Dependent Protein Kinases; D000091162:AMP-Activated Protein Kinase Kinases; D055372:AMP-Activated Protein Kinases; D006655:Histone Deacetylases
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