In:
Diabetes, American Diabetes Association, Vol. 52, No. 4 ( 2003-04-01), p. 974-983
Abstract:
Glucose can activate the mitogen-activated kinases, Erk-1/2, and the ribosomal-S6 kinase, p70S6K, in β-cells, contributing to an increase in mitogenesis. However, the signaling mechanism by which glucose induces Erk-1/2 and p70S6K phosphorylation activation is undefined. Increased glucose metabolism increases [Ca2+]i and [cAMP] , and it was investigated if these secondary signals were linked to glucose-induced Erk-1/2 and p70S6K activation in pancreatic β-cells. Blocking Ca2+ influx with verapamil, or inhibiting protein kinase A (PKA) with H89, prevented glucose-induced Erk-1/2 phosphorylation. Increasing cAMP levels by GLP-1 potentiated glucose-induced Erk-1/2 phosphorylation via PKA activation. Elevation of [Ca2+]i by glyburide potentiated Erk-1/2 phosphorylation, which was also inhibited by H89, suggesting increased [Ca2+] i preceded PKA for glucose-induced Erk-1/2 activation. Adenoviral-mediated expression of dominant negative Ras in INS-1 cells decreased IGF-1-induced Erk-1/2 phosphorylation but had no effect on that by glucose. Collectively, our study indicates that a glucose-induced rise in [Ca2+]i leads to cAMP-induced activation of PKA that acts downstream of Ras and upstream of the MAP/Erk kinase, MEK, to mediate Erk-1/2 phosphorylation via phosphorylation activation of Raf-1. In contrast, glucose-induced p70S6K activation, in the same β-cells, was mediated by a distinct signaling pathway independent of Ca2+/cAMP, most likely via mTOR-kinase acting as an “ATP-sensor.”
Type of Medium:
Online Resource
ISSN:
0012-1797
,
1939-327X
DOI:
10.2337/diabetes.52.4.974
Language:
English
Publisher:
American Diabetes Association
Publication Date:
2003
detail.hit.zdb_id:
1501252-9
Permalink