The tumor suppressor kinase LKB1 activates the downstream kinases SIK2 and SIK3 to stimulate nuclear export of class IIa histone deacetylases.

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.
Mesh Terms:
14-3-3 Proteins, Animals, Cell Line, Tumor, Cyclic AMP-Dependent Protein Kinases, Cytoplasm, Genes, Reporter, HEK293 Cells, HeLa Cells, Histone Deacetylases, Humans, Mice, Protein Binding, Protein Kinases, Protein-Serine-Threonine Kinases, Signal Transduction
J. Biol. Chem.
Date: Mar. 29, 2013
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