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cAMP-elevation mediated by β-adrenergic stimulation inhibits salt-inducible kinase (SIK) 3 activity in adipocytes.

Berggreen, Christine LU ; Henriksson, Emma LU ; Jones, Helena LU ; Morrice, Nicholas and Göransson, Olga LU (2012) In Cellular Signalling 24(9). p.1863-1871
Abstract
Salt-inducible kinase (SIK) 3 is a virtually unstudied, ubiquitously expressed serine/threonine kinase, belonging to the AMP-activated protein kinase (AMPK)-related family of kinases, all of which are regulated by LKB1 phosphorylation of a threonine residue in their activation (T)-loops. Findings in adrenal cells have revealed a role for cAMP in the regulation of SIK1, and recent findings suggest that insulin can regulate an SIK isoform in Drosophila. As cAMP has important functions in adipocytes, mainly in the regulation of lipolysis, we have evaluated a potential role for cAMP, as well as for insulin, in the regulation of SIK3 in these cells. We establish that raised cAMP levels in response to forskolin and the β-adrenergic receptor... (More)
Salt-inducible kinase (SIK) 3 is a virtually unstudied, ubiquitously expressed serine/threonine kinase, belonging to the AMP-activated protein kinase (AMPK)-related family of kinases, all of which are regulated by LKB1 phosphorylation of a threonine residue in their activation (T)-loops. Findings in adrenal cells have revealed a role for cAMP in the regulation of SIK1, and recent findings suggest that insulin can regulate an SIK isoform in Drosophila. As cAMP has important functions in adipocytes, mainly in the regulation of lipolysis, we have evaluated a potential role for cAMP, as well as for insulin, in the regulation of SIK3 in these cells. We establish that raised cAMP levels in response to forskolin and the β-adrenergic receptor agonist CL 316,243 induce a phosphorylation of SIK3 in HEK293 cells and primary adipocytes. This phosphorylation coincides with increased 14-3-3 binding to SIK3 in these cell types. Our findings also show that cAMP-elevation results in reduced SIK3 activity in adipocytes. Phosphopeptide mapping and site-directed mutagenesis reveal that the cAMP-mediated regulation of SIK3 appears to depend on three residues, T469, S551 and S674, that all contribute to some extent to the cAMP-induced phosphorylation and 14-3-3-binding. As the cAMP-induced regulation can be reversed with the protein kinase A (PKA) inhibitor H89, and a role for other candidate kinases, including PKB and RSK, could be excluded, we believe that PKA is the kinase responsible for SIK3 regulation in response to elevated cAMP levels. Our findings of cAMP-mediated regulation of SIK3 suggest that SIK3 may mediate some of the effects of this important second messenger in adipocytes. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Adipocyte, AMPK, 14-3-3, SIK3, PKA, cAMP
in
Cellular Signalling
volume
24
issue
9
pages
1863 - 1871
publisher
Elsevier
external identifiers
  • wos:000306621000017
  • pmid:22588126
  • scopus:84862658489
ISSN
1873-3913
DOI
10.1016/j.cellsig.2012.05.001
language
English
LU publication?
yes
id
df0f3cf3-09f7-46b4-a419-ae8f01a5da2a (old id 2608824)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/22588126?dopt=Abstract
date added to LUP
2012-06-03 20:00:30
date last changed
2017-07-23 03:01:54
@article{df0f3cf3-09f7-46b4-a419-ae8f01a5da2a,
  abstract     = {Salt-inducible kinase (SIK) 3 is a virtually unstudied, ubiquitously expressed serine/threonine kinase, belonging to the AMP-activated protein kinase (AMPK)-related family of kinases, all of which are regulated by LKB1 phosphorylation of a threonine residue in their activation (T)-loops. Findings in adrenal cells have revealed a role for cAMP in the regulation of SIK1, and recent findings suggest that insulin can regulate an SIK isoform in Drosophila. As cAMP has important functions in adipocytes, mainly in the regulation of lipolysis, we have evaluated a potential role for cAMP, as well as for insulin, in the regulation of SIK3 in these cells. We establish that raised cAMP levels in response to forskolin and the β-adrenergic receptor agonist CL 316,243 induce a phosphorylation of SIK3 in HEK293 cells and primary adipocytes. This phosphorylation coincides with increased 14-3-3 binding to SIK3 in these cell types. Our findings also show that cAMP-elevation results in reduced SIK3 activity in adipocytes. Phosphopeptide mapping and site-directed mutagenesis reveal that the cAMP-mediated regulation of SIK3 appears to depend on three residues, T469, S551 and S674, that all contribute to some extent to the cAMP-induced phosphorylation and 14-3-3-binding. As the cAMP-induced regulation can be reversed with the protein kinase A (PKA) inhibitor H89, and a role for other candidate kinases, including PKB and RSK, could be excluded, we believe that PKA is the kinase responsible for SIK3 regulation in response to elevated cAMP levels. Our findings of cAMP-mediated regulation of SIK3 suggest that SIK3 may mediate some of the effects of this important second messenger in adipocytes.},
  author       = {Berggreen, Christine and Henriksson, Emma and Jones, Helena and Morrice, Nicholas and Göransson, Olga},
  issn         = {1873-3913},
  keyword      = {Adipocyte,AMPK,14-3-3,SIK3,PKA,cAMP},
  language     = {eng},
  number       = {9},
  pages        = {1863--1871},
  publisher    = {Elsevier},
  series       = {Cellular Signalling},
  title        = {cAMP-elevation mediated by β-adrenergic stimulation inhibits salt-inducible kinase (SIK) 3 activity in adipocytes.},
  url          = {http://dx.doi.org/10.1016/j.cellsig.2012.05.001},
  volume       = {24},
  year         = {2012},
}