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Molecular and Cellular Biology, March 2004, p. 2169-2180, Vol. 24, No. 5
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.5.2169-2180.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

A Transforming Growth Factor ß-Induced Smad3/Smad4 Complex Directly Activates Protein Kinase A

Lizhi Zhang,1 Chao Jun Duan,1 Charles Binkley,1 Gangyong Li,1 Michael D. Uhler,2 Craig D. Logsdon,3 and Diane M. Simeone1,3*

Departments of Surgery,1 Biological Chemistry,2 Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, Michigan 481093

Received 9 May 2003/ Returned for modification 1 July 2003/ Accepted 26 November 2003

Transforming growth factor ß (TGFß) interacts with cell surface receptors to initiate a signaling cascade critical in regulating growth, differentiation, and development of many cell types. TGFß signaling involves activation of Smad proteins which directly regulate target gene expression. Here we show that Smad proteins also regulate gene expression by using a previously unrecognized pathway involving direct interaction with protein kinase A (PKA). PKA has numerous effects on growth, differentiation, and apoptosis, and activation of PKA is generally initiated by increased cellular cyclic AMP (cAMP). However, we found that TGFß activates PKA independent of increased cAMP, and our observations support the conclusion that there is formation of a complex between Smad proteins and the regulatory subunit of PKA, with release of the catalytic subunit from the PKA holoenzyme. We also found that the activation of PKA was required for TGFß activation of CREB, induction of p21Cip1, and inhibition of cell growth. Taken together, these data indicate an important and previously unrecognized interaction between the TGFß and PKA signaling pathways.

* Corresponding author. Mailing address: TC 2922D, Box 0331, University of Michigan Medical Center, 1500 E. Medical Center Dr., Ann Arbor, MI 48109. Phone: (734) 615-1600. Fax: (734) 936-5830. E-mail: simeone{at}umich.edu.

Molecular and Cellular Biology, March 2004, p. 2169-2180, Vol. 24, No. 5
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.5.2169-2180.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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