Expression of cAMP-regulated guanine nucleotide exchange factors in pancreatic beta-cells.
The insulinotropic hormone glucagon-like peptide-1 (GLP-1) binds to a Gs-coupled receptor on pancreatic beta-cells and potentiates glucose-induced insulin secretion, insulin gene transcription, and beta-cell growth. These stimulatory effects have been attributed to the elevation of intracellular cAMP levels, though it is now apparent that some stimulatory effects of GLP-1 occur independently of the cAMP-mediated activation of protein kinase A (PKA). The nature of this alternative, PKA-independent signaling pathway remains unknown. Here we present evidence for the expression of type 1 and type 2 cAMP-regulated guanine nucleotide exchange factors (cAMP-GEFs) in beta-cells. GEFs are activated by their binding of cAMP. Because cAMP-GEFs activate Ras/MAPK proliferation signaling pathways, they may play an important role in PKA-independent, GLP-1-mediated, signaling pathways in the regulation of beta-cell growth and differentiation.
Leech
C A
CA
Laboratory of Molecular Endocrinology, Howard Hughes Medical Institute, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
Holz
G G
GG
Chepurny
O
O
Habener
J F
JF
D000818:Animals; D015153:Blotting, Western; D002454:Cell Differentiation; D002455:Cell Division; D000242:Cyclic AMP / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D018076:DNA, Complementary / Q000378:metabolism; D004789:Enzyme Activation; D005934:Glucagon / Q000378:metabolism; D052216:Glucagon-Like Peptide 1; D005947:Glucose / Q000378:metabolism; D020662:Guanine Nucleotide Exchange Factors / Q000096:biosynthesis*; D006801:Humans; D007328:Insulin / Q000378:metabolism; D007515:Islets of Langerhans / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D008954:Models, Biological; D010446:Peptide Fragments / Q000378:metabolism; D016133:Polymerase Chain Reaction; D011485:Protein Binding; D011498:Protein Precursors / Q000378:metabolism; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D014158:Transcription, Genetic; D020827:rap1 GTP-Binding Proteins / Q000378:metabolism; D018631:ras Proteins / Q000378:metabolism
D018076:DNA, Complementary; D020662:Guanine Nucleotide Exchange Factors; D007328:Insulin; D010446:Peptide Fragments; D011498:Protein Precursors; D052216:Glucagon-Like Peptide 1; D005934:Glucagon; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D020827:rap1 GTP-Binding Proteins; D018631:ras Proteins; D005947:Glucose