Abstract
Signaling via cAMP plays an important role in apical cell surface dynamics in epithelial cells. In hepatocytes, elevated levels of cAMP as well as extracellular oncostatin M stimulate apical lumen development in a manner that depends on protein kinase A (PKA) activity. However, neither the identity of PKA isoforms involved nor the mechanisms of the cross-talk between oncostatin M and cAMP/PKA signaling pathways have been elucidated. Here we demonstrate that oncostatin M and PKA signaling converge at the level of the PKA holoenzyme downstream of oncostatin M-stimulated MAPK activation. Experiments were performed with chemically modified cAMP analogues that preferentially target regulatory subunit (R) I or RII holoenzymes, respectively, in hepatocytes. The data suggest that the dissociation of RI- but not RII-containing holoenzymes, as well as catalytic activity of PKA, is required for apical lumen development in response to elevated levels of cAMP and oncostatin M. However, oncostatin M signaling does not stimulate PKA holoenzyme dissociation in living cells. Based on pharmacological and cell biological studies, it is concluded that RI-controlled PKA activity is essential for cAMP- and oncostatin M-stimulated development of apical bile canalicular lumens.
Original language | English |
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Pages (from-to) | 20773-80 |
Number of pages | 8 |
Journal | Journal of Biological Chemistry |
Volume | 284 |
Issue number | 31 |
DOIs | |
Publication status | Published - 31 Jul 2009 |
Keywords
- Adenylate Cyclase
- Bile Canaliculi
- Cell Line, Tumor
- Cell Nucleus
- Cell Polarity
- Cell Survival
- Cyclic AMP
- Cyclic AMP-Dependent Protein Kinase RIIalpha Subunit
- Cyclic AMP-Dependent Protein Kinase RIalpha Subunit
- Energy Transfer
- Enzyme Activation
- Enzyme Activators
- Enzyme Inhibitors
- Hepatocytes
- Holoenzymes
- Humans
- Isoenzymes
- Mitogen-Activated Protein Kinase 3
- Oncostatin M
- Phosphorylation
- Recombinant Fusion Proteins