PKD in intestinal epithelial cells: rapid activation by phorbol esters, LPA, and angiotensin through PKC.
Protein kinase C (PKC) is implicated in the regulation of multiple important functions in intestinal epithelial cells, but the downstream signaling targets of PKCs in these cells remain poorly characterized. Here we report that treatment of normal rat intestinal cell lines IEC-6 and IEC-18 with phorbol 12,13-dibutyrate (PDBu) led to a rapid and striking PKC-dependent activation of protein kinase D (PKD; also known as PKCmu). Unlike conventional and novel PKCs, PKD did not undergo downregulation in response to prolonged (24 h) exposure of IEC-6 or IEC-18 cells to PDBu. PKD was also rapidly activated in these cells by lysophosphatidic acid (LPA) or angiotensin in a concentration-dependent fashion via a PKC-dependent pathway. EC(50) values were 0.1 microM and 2 nM for LPA and angiotensin II, respectively. LPA-induced PKD activation was prevented selectively by treatment with pertussis toxin. PKD activation was tightly associated with an increase in PKD autophosphorylation at serine 916. Our results identify PKD as a novel early point of convergence and integration of G(i) and G(q) signaling in intestinal epithelial cells.
Department of Medicine, UCLA School of Medicine and Molecular Biology Institute, Los Angeles, CA 90095, USA.
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D000595:Amino Acid Sequence; D000809:Angiotensins / Q000494:pharmacology*; D000818:Animals; D002273:Carcinogens / Q000494:pharmacology*; D002460:Cell Line; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000378:metabolism; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D020962:Heterotrimeric GTP-Binding Proteins / Q000378:metabolism; D007413:Intestinal Mucosa / Q000166:cytology / Q000201:enzymology*; D008246:Lysophospholipids / Q000494:pharmacology*; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000737:chemistry / Q000494:pharmacology; D015240:Phorbol 12,13-Dibutyrate / Q000494:pharmacology*; D010766:Phosphorylation; D011493:Protein Kinase C / Q000096:biosynthesis / Q000737:chemistry / Q000378:metabolism*; D051381:Rats; D015398:Signal Transduction / Q000502:physiology; D014662:Vasoconstrictor Agents / Q000494:pharmacology*
D000809:Angiotensins; D002273:Carcinogens; D008246:Lysophospholipids; D010446:Peptide Fragments; D014662:Vasoconstrictor Agents; D015240:Phorbol 12,13-Dibutyrate; C089212:protein kinase D; D011493:Protein Kinase C; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D020962:Heterotrimeric GTP-Binding Proteins