PMID- 10567568
OWN - NLM
STAT- MEDLINE
DCOM- 20000106
LR  - 20190508
IS  - 0270-7306 (Print)
IS  - 0270-7306 (Linking)
VI  - 19
IP  - 12
DP  - 1999 Dec
TI  - Glycogen synthase kinase 3 is an insulin-regulated C/EBPalpha kinase.
PG  - 8433-41
AB  - CCAAT/enhancer binding protein alpha (C/EBPalpha) is a transcription factor
      involved in creating and maintaining the adipocyte phenotype. We have shown
      previously that insulin stimulates dephosphorylation of C/EBPalpha in 3T3-L1
      adipocytes. Studies to identify the insulin-sensitive sites of phosphorylation
      reveal that a C/EBPalpha peptide (amino acids H215 to K250) is phosphorylated on 
      T222, T226, and S230 in vivo. The context of these phosphoamino acids implicates 
      glycogen synthase kinase 3 (GSK3), whose activity is known to be repressed in
      response to insulin, as a potential kinase for phosphorylation of T222 and T226. 
      Accordingly, GSK3 phosphorylates the predicted region of C/EBPalpha on threonine 
      in vitro, and GSK3 uses C/EBPalpha as a substrate in vivo. In addition, the
      effect of pharmacological agents on GSK3 activity correlates with regulation of
      C/EBPalpha phosphorylation. Treatment of 3T3-L1 adipocytes with the
      phosphatidylinositol 3-kinase inhibitor wortmannin results in phosphorylation of 
      C/EBPalpha, whereas treatment with the GSK3 inhibitor lithium results in
      dephosphorylation of C/EBPalpha. Collectively, these data indicate that insulin
      stimulates dephosphorylation of C/EBPalpha on T222 and T226 through inactivation 
      of GSK3. Since dephosphorylation of C/EBPalpha in response to lithium is blocked 
      by okadaic acid, strong candidates for the T222 and T226 phosphatase are protein 
      phosphatases 1 and 2a. Treatment of adipocytes with insulin alters the protease
      accessibility of widespread sites within the N terminus of C/EBPalpha, consistent
      with phosphorylation causing profound conformational changes. Finally,
      phosphorylation of C/EBPalpha and other substrates by GSK3 may be required for
      adipogenesis, since treatment of differentiating preadipocytes with lithium
      inhibits their conversion to adipocytes.
FAU - Ross, S E
AU  - Ross SE
AD  - Department of Physiology, University of Michigan Medical School, Ann Arbor, MI
      48109-0622, USA.
FAU - Erickson, R L
AU  - Erickson RL
FAU - Hemati, N
AU  - Hemati N
FAU - MacDougald, O A
AU  - MacDougald OA
LA  - eng
GR  - R01 DK051563/DK/NIDDK NIH HHS/United States
GR  - R01DK51563/DK/NIDDK NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - Mol Cell Biol
JT  - Molecular and cellular biology
JID - 8109087
RN  - 0 (Androstadienes)
RN  - 0 (CCAAT-Enhancer-Binding Proteins)
RN  - 0 (DNA-Binding Proteins)
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (Insulin)
RN  - 0 (Insulin Antagonists)
RN  - 0 (Nuclear Proteins)
RN  - 0 (Phosphoamino Acids)
RN  - 0 (Recombinant Fusion Proteins)
RN  - 0 (Transcription Factors)
RN  - 9FN79X2M3F (Lithium)
RN  - EC 2.7.11.- (Glycogen Synthase Kinases)
RN  - EC 2.7.11.17 (Calcium-Calmodulin-Dependent Protein Kinases)
RN  - EC 2.7.11.26 (Glycogen Synthase Kinase 3)
RN  - XVA4O219QW (Wortmannin)
SB  - IM
MH  - 3T3 Cells
MH  - Androstadienes/metabolism/pharmacology
MH  - Animals
MH  - CCAAT-Enhancer-Binding Proteins
MH  - Calcium-Calmodulin-Dependent Protein Kinases/*metabolism
MH  - Cell Differentiation
MH  - Cell Line, Transformed
MH  - DNA-Binding Proteins/genetics/*metabolism
MH  - Enzyme Inhibitors/metabolism/pharmacology
MH  - Glycogen Synthase Kinase 3
MH  - Glycogen Synthase Kinases
MH  - Humans
MH  - Insulin/*metabolism/pharmacology
MH  - Insulin Antagonists/metabolism/pharmacology
MH  - Lithium/metabolism/pharmacology
MH  - Mice
MH  - Nuclear Proteins/genetics/*metabolism
MH  - Phosphoamino Acids
MH  - Phosphorylation
MH  - Recombinant Fusion Proteins/genetics/metabolism
MH  - Transcription Factors/genetics/*metabolism
MH  - Wortmannin
PMC - PMC84944
EDAT- 1999/11/24 00:00
MHDA- 1999/11/24 00:01
CRDT- 1999/11/24 00:00
PHST- 1999/11/24 00:00 [pubmed]
PHST- 1999/11/24 00:01 [medline]
PHST- 1999/11/24 00:00 [entrez]
AID - 10.1128/mcb.19.12.8433 [doi]
PST - ppublish
SO  - Mol Cell Biol. 1999 Dec;19(12):8433-41. doi: 10.1128/mcb.19.12.8433.