Submitted on October 25, 2007
Accepted on April 23, 2008
Regulation of Transforming Growth Factor 
-Induced Responses by Protein Kinase A in Pancreatic Acinar Cells
Huibin Yang1, Cheong J Lee1, Lizhi Zhang2, Maria Dolors Sans3, and Diane M. Simeone1*
1 General Surgery and Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan, United States
2 Pathology, Mayo Clinic, Rochester, Minnesota, United States
3 Physiology, University of Michigan, Ann Arbor, Michigan, United States
* To whom correspondence should be addressed. E-mail: simeone{at}umich.edu.
TGF
is an important regulator of growth and differentiation in the pancreas and has been implicated in pancreatic tumorigenesis. We have recently demonstrated that TGF can activate protein kinase A (PKA) in mink lung epithelial cells (Mol Cell Biol 24: 2169-2180, 2004). In this study, we sought to determine if TGF activates PKA in pancreatic acinar cells, the mechanism by which PKA is activated, and PKA's role in TGF-mediated growth regulatory responses. TGF rapidly activated PKA in pancreatic acini, while having no effect on intracellular cAMP levels. Co-immunoprecipitation experiments demonstrated a physical interaction between a Smad3/Smad4 complex and the regulatory subunits of PKA. TGF also induced activation of the PKA-dependent transcription factor CREB. Both the specific PKA inhibitor H89 and PKI peptide significantly blocked TGF's ability to activate PKA and CREB. TGF-mediated growth inhibition and TGF-induced p21 and SnoN expression in pancreatic acinar cells were blocked by H89 and PKI peptide. This study demonstrates that this novel crosstalk between TGF and PKA signaling pathways may play an important role in regulating TGF signaling in the pancreas.
