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Molecular and Cellular Biology, December 1999, p. 8433-8441, Vol. 19, No. 12
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Glycogen Synthase Kinase 3 Is an Insulin-Regulated C/EBPalpha Kinase

Sarah E. Ross, Robin L. Erickson, Nahid Hemati, and Ormond A. MacDougald*

Department of Physiology, University of Michigan Medical School, Ann Arbor, MI 48109-0622

Received 8 July 1999/Returned for modification 25 August 1999/Accepted 8 September 1999

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.

* Corresponding author. Mailing address: Department of Physiology, University of Michigan Medical School, 1301 E. Catherine Rd., Ann Arbor, MI 48109-0622. Phone: (734) 647-4880. Fax: (734) 936-8813. E-mail: macdouga{at}umich.edu.

Molecular and Cellular Biology, December 1999, p. 8433-8441, Vol. 19, No. 12
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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