Differential Activation Mechanisms of Erk-1/2 and p70S6K by Glucose in Pancreatic β-Cells

I Briaud, MK Lingohr, LM Dickson, CE Wrede… - Diabetes, 2003 - Am Diabetes Assoc
I Briaud, MK Lingohr, LM Dickson, CE Wrede, CJ Rhodes
Diabetes, 2003Am Diabetes Assoc
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 …
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.”
Am Diabetes Assoc