Regulation of SIK2 Activity by Acetylation
Date Issued
2007
Date
2007
Author(s)
Sun, Huei-Yu
DOI
en-US
Abstract
Salt-inducible kinase 2 (SIK2), a serine/threonine protein kinase, belongs to members of the AMP-activated protein kinase (AMPK) family. It is highly expressed in mature adipocytes and regulates the early phase of insulin-signaling during adipocyte differentiation. So far, the physiological substrates of SIK2 are not well-understood, except for IRS-1 and TORC2. Insulin receptor substrate-1 (IRS-1), which is reported to play important roles in the insulin-signaling in the adipose tissue, is thought to be a potential endogenous substrate of SIK2 at serine 794, whereas TOR2, participating in the regulation of CREB signaling, is phosphorylated at serine 171.
In the present study, we have identified that p97/VCP, an AAA-ATPase involved in a variety of cellular processes, interacts with SIK2 physically and functionally. Moreover, SIK2 and p97/VCP are co-localized to the ER membrane. The interaction between SIK2 and p97/VCP modulates p97/VCP-dependent ER-associated degradation (ERAD). Lysine 53, a site located in the kinase ATP-binding domain of SIK2, is found to be acetylated. We have previously described that lysine 53 acetylation results in the inhibition of the kinase activity of SIK2. The acetylation mimetic mutant K53Q showed accumulation of the ERAD substrate CD3δ. We further identified that p300 /CBP and HDAC6 are responsible for the acetylation and deacetylation of lysine 53 of SIK2. In conclusion, our results demonstrate that acetylation of SIK2 negatively regulates its kinase activity, thus attenuates the degradation of the ERAD substrates.
Subjects
SIK2
p97/VCP
乙醯化作用
p300/CBP
HDAC6
ERAD
Acetylation
Type
other
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