Abstract
Insulin binding results in rapid phosphorylation of insulin receptor substrate-1 to activate p21ras and mitogen-activated protein kinase. Insulin also activates the ribosomal protein S6 kinase (pp70 S6 kinase) independently of the Ras pathway. Chronic (18 h) treatment of L6 muscle cells with insulin increases glucose transport activity severalfold due to biosynthetic elevation of the GLUT1 and GLUT3 but not the GLUT4 glucose transporters. Here we investigate the roles of p21ras and pp70 S6 kinase in the insulin-mediated increases in GLUT1 and GLUT3 expression. L6 cells were transfected with the dominant negative Ras(S17N) under the control of a dexamethasone-inducible promoter. Induction of Ras(S17N) failed to block the insulin-mediated increase in GLUT1 glucose transporter protein and mRNA; however, it abrogated the insulin-mediated increase in GLUT3 glucose transporter protein and mRNA. Inhibition of pp70 S6 kinase by rapamycin, on the other hand, eliminated the insulin-mediated increase in GLUT1 but had no effect on that of GLUT3 in both parental and Ras(S17N) transfected L6 cells. These results suggest that the biosynthetic regulation of glucose transporters is differentially determined, with pp70 S6 kinase and p21ras playing active roles in the insulin-stimulated increases in GLUT1 and GLUT3, respectively.
Highlights
Insulin mediates a wide spectrum of biological responses including stimulation of glucose influx and metabolism in muscle and adipocytes, transport of amino acids, transcription of specific genes and mitogenesis [1, 2]
Using a constructed L6 cell line transfected with a dominant negative Ras, Ras(S17N) under the control of a dexamethasone-inducible promoter [25], and using rapamycin, a specific inhibitor of pp70 S6 kinase [11, 26], we investigated the roles of p21ras and pp70 S6 kinase in the insulin-mediated regulation of expression of GLUT1 and GLUT3 protein and mRNA
Insulin Stimulation of GLUT1 Expression Is Mediated by pp70 S6 Kinase but Not by p21ras—L6 cells transfected with dominant negative Ras(S17N) under the control of a dexamethasone-inducible promoter were treated with/without dexamethasone for 24 h prior to chronic (18 h) exposure to insulin
Summary
Insulin mediates a wide spectrum of biological responses including stimulation of glucose influx and metabolism in muscle and adipocytes, transport of amino acids, transcription of specific genes and mitogenesis [1, 2]. These are determined by signals initiated by insulin binding, leading to rapid autophosphorylation of receptor tyrosine residues [3] and tyrosine phos-. We observed that sustained insulin-like growth factor-1 treatment leads to an increase in GLUT3 mRNA and protein levels [22]. Similar observations on GLUT1 and GLUT4 have been made in 3T3-F442A adipocytes [23]
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