Interaction between Salt-inducible kinase 2 and protein phosphatase 2A regulates the activity of calcium/calmodulin-dependent protein kinase i and protein phosphatase methylesterase-1

Salt-inducible kinase 2 (SIK2) is the only AMP-activated kinase (AMPK) family member known to interact with protein phosphatase 2 (PP2A). However, the functional aspects of this complex are largely unknown. Herewereport that the SIK2+PP2Acomplex preserves both kinaseandphosphatase activities. In this capacity, SIK2 attenuates the association of the PP2A repressor, the protein phosphatase methylesterase-1 (PME-1), thus preserving the methylation status of the PP2A catalytic subunit. Furthermore, the SIK2+PP2A holoenzyme complex dephosphorylates and inactivates Ca²⁺/calmodulin-dependent protein kinase I (CaMKI), an upstream kinase for phosphorylating PME-1/Ser15. The functionally antagonistic SIK2+PP2A and CaMKI and PME-1networks thus constitute a negative feedback loop that modulates the phosphatase activity of PP2A. Depletion of SIK2 led to disruption of the SIK2+PP2A complex, activation of CaMKI, and downstream effects, including phosphorylation of HDAC5/Ser259, sequestration of HDAC5 in the cytoplasm, and activation of myocyte-specific enhancer factor 2C (MEF2C)-mediated gene expression. These results suggest that the SIK2+PP2A complex functions in the regulation of MEF2C-dependent transcription. Furthermore, this study suggests that the tightly linked regulatory loop comprised of the SIK2+PP2A and CaMKI and PME-1 networks may function in fine-tuning cell proliferation and stress response.