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. Here we report that the SIK2-PP2A complex preserves both kinase and phosphatase 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/Ser(15). The functionally antagonistic SIK2-PP2A and CaMKI and PME-1 networks 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/Ser(259), 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.
Chia-Wei
CW
Lee
Fu-Chia
FC
Yang
Hsin-Yun
HY
Chang
Hanyi
H
Chou
Bertrand Chin-Ming
BC
Tan
Sheng-Chung
SC
Lee
D054729:Calcium-Calmodulin-Dependent Protein Kinase Type 1; D002265:Carboxylic Ester Hydrolases / Q000235:genetics / Q000378:metabolism*; D049109:Cell Proliferation / Q000502:physiology*; D003593:Cytoplasm / Q000201:enzymology / Q000235:genetics; D017353:Gene Deletion; D005786:Gene Expression Regulation / Q000502:physiology; D057809:HEK293 Cells; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism; D006801:Humans; D064326:MEF2 Transcription Factors / Q000235:genetics / Q000378:metabolism; D009097:Multienzyme Complexes / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation / Q000502:physiology; D054648:Protein Phosphatase 2 / Q000235:genetics / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic / Q000502:physiology
D064326:MEF2 Transcription Factors; C578040:MEF2C protein, human; D009097:Multienzyme Complexes; C551842:salt-inducible kinase-2, human; D017346:Protein Serine-Threonine Kinases; C517596:CAMK1 protein, human; D054729:Calcium-Calmodulin-Dependent Protein Kinase Type 1; D002265:Carboxylic Ester Hydrolases; C119357:protein phosphatase methylesterase-1; C517189:PPP2CA protein, human; D054648:Protein Phosphatase 2; C404500:HDAC5 protein, human; D006655:Histone Deacetylases