Protein kinase Cα mediates cAMP response element-binding protein activation by retinoic acid in normal human bronchial epithelial cells.

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Vitamin A and its metabolite retinoic acid (RA) are essential elements in normal lung development and differentiation of lung epithelial cells. We previously showed that RA rapidly activated cAMP response element-binding protein (CREB) in a nonclassical RA signal transduction pathway without using its conventional RA receptor or retinoid X receptor in normal human tracheobronchial epithelial (NHTBE) cells. In the present study, we further demonstrated this nonclassical effect of RA on the activation of CREB by showing that RA rapidly activates the α isozyme of protein kinase C (PKC) and transmits an activation signal to CREB via the Raf/mitogen-activated protein kinase kinase (MEK) /extracellular regulated kinase (ERK)/p90 ribosomal S6 kinase (RSK) pathway. RA rapidly activated PKCα, the major conventional PKC isozyme expressed in NHTBE cells. Activated PKCα was immediately translocated from the cytoplasm to the plasma and perinuclear membranes, and it stimulated a downstream linear signaling cascade involving Raf/MEK/ERK/RSK. Finally, activated RSK but not ERK translocated from the cytoplasm to the nucleus, where activated RSK phosphorylates CREB. The normal function and intactness of this nonclassical RA signaling pathway may play an important role in mediating early biological effects of RA in normal differentiation of bronchial epithelia. * Supported by R01-HL-077556 (NHLBI/NIH).