Functional interaction between SIK2 and PP2A
Date Issued
2012
Date
2012
Author(s)
Lee, Chia-Wei
Abstract
Salt-inducible kinase 2 (SIK2) is a member of AMPK family, SIK subfamily. Members of AMPK family play wide array of functions ranging from sensing energy status, stress response to apoptosis and autophagy. SIK2 is the only member of AMPK family that can interact with PP2A and VCP/P97. However, the function of this SIK2-PP2A complex is largely unknown. It was demonstrated in cancer cells that SIK2 is important protein degradation by both UPS and autophagy. SIK2 knockdown resulted in decreasing both levels of PP2Ac and carboxymethylated PP2Ac (PP2Ac/L309Me). SIK2 knockdown also resulted in increasing the phosphorylation of Bcl-2/S70. I identified the phosphorylation of PME-1/S15 was positively regulated by knockdown of SIK2. The enzymatic activity of PP2A may be regulated by heterotrimer formation in which recruiting the substrate-specific regulatory B subunit is believed to be the crucial step. A novel PP2Ac subunit C-terminal Leucine modification by LCMT1-mediated carboxymethylation is also essential for the catalytic activity of PP2A. PME-1, a carboxymethylesterase specific for the removal of PP2Ac/L309Me could complex with PP2Ac and inhibits its activity. I have also uncovered that SIK2-PP2A complex preserves the phosphatase activity. PME-1 is excluded from that complex. I also showed that SIK2 knockdown resulted in the activation of CaMK1 and phosphorylation of PME-1/S15. It turned out that the activity of CaMK1 is negatively regulated by PP2A in a SIK2-dependent manner. I have demonstrated that PME-1/S15 is the target of CaMK1. Unexpectedly, kinase-dead mutant of SIK2 (i.e., SIK2/K49M) could also form SIK2/K49M-PP2A complex and preserve the PP2A activity. Together, these results suggest that one of the functions of SIK2 may be an adaptor. PP2A activity is protected in the SIK2-PP2A complex from the inhibition of PME-1. The Ca2+-dependent activation of CaMK1 during UPS- or autophagosome-induction and phosphorylation of PME-1/S15 may be regulated by PP2A-dependent feedback inhibition. Taken together, these findings suggest that SIK2 is an important regulator for ER homeostasis through maintaining PP2A activity and the level of antiapoptotic protein Bcl-2 in the ER membrane.
Subjects
SIK2
PP2A
PME-1
ER-stress
CaMK1
BcL-2
apoptosis
SDGs
Type
thesis
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