cAMP-dependent phosphorylation of PTB1 promotes the expression of insulin secretory granule proteins in beta cells.
Glucose stimulates the exocytosis of insulin secretory granules of pancreatic beta cells. Granule stores are quickly refilled by activation of posttranscriptional mechanisms that enhance the biosynthesis of granule components. Rapid replacement of granules is important to sustain insulin secretion, since new granules appear to be preferentially released. Posttranscriptional regulation of granule biogenesis includes the glucose-induced nucleocytoplasmic translocation of polypyrimidine tract binding protein 1 (PTB1), which binds mRNAs encoding granule proteins, and thus promotes their stabilization and translation. Glucagon-like peptide 1 (GLP-1) potentiates glucose-stimulated insulin gene expression and secretion by increasing cAMP levels in beta cells. Here, we show that elevation of cAMP levels causes the protein kinase A-dependent phosphorylation and nucleocytoplasmic translocation of PTB1, thereby preventing the rapid degradation of insulin mRNA and enhancing the expression of various granule proteins. Taken together, these findings identify PTB1 as a common downstream target of glucose and GLP-1 for the posttranscriptional upregulation of granule biogenesis.
Knoch
Klaus-Peter
KP
Laboratory of Experimental Diabetology, Medical School, Dresden University of Technology, Fetscherstrasse 74, 01307 Dresden, Germany.
Meisterfeld
Ronny
R
Kersting
Stephan
S
Bergert
Hendrik
H
Altkrüger
Anke
A
Wegbrod
Carolin
C
Jäger
Melanie
M
Saeger
Hans-Detlev
HD
Solimena
Michele
M
D000818:Animals; D003001:Cloning, Molecular; D000242:Cyclic AMP / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D017931:DNA Primers; D018076:DNA, Complementary / Q000235:genetics; D005260:Female; D005786:Gene Expression Regulation / Q000502:physiology*; D052216:Glucagon-Like Peptide 1 / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D034441:Heterogeneous-Nuclear Ribonucleoproteins; D007150:Immunohistochemistry; D007328:Insulin / Q000096:biosynthesis*; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D008156:Luciferases; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D038941:Polypyrimidine Tract-Binding Protein; D034622:RNA Interference; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D020133:Reverse Transcriptase Polymerase Chain Reaction; D022142:Secretory Vesicles / Q000378:metabolism
D017931:DNA Primers; D018076:DNA, Complementary; D034441:Heterogeneous-Nuclear Ribonucleoproteins; D007328:Insulin; D009124:Muscle Proteins; C475523:Ptbp1 protein, rat; D016601:RNA-Binding Proteins; D038941:Polypyrimidine Tract-Binding Protein; D052216:Glucagon-Like Peptide 1; D000242:Cyclic AMP; D008156:Luciferases; D017868:Cyclic AMP-Dependent Protein Kinases; D005947:Glucose