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© 2002 by the American Diabetes Association, Inc.
Activation of IRS-2—Mediated Signal Transduction by IGF-1, but not TGF-
or EGF, Augments Pancreatic ß-Cell Proliferation
1 Pacific Northwest Research Institute, Seattle, Washington, and the Department of Pharmacology, University of Washington, Seattle, Washington
2 Stem Cell Pharmaceuticals Inc., Seattle, Washington
Transforming growth factor (TGF)-
- and epidermal growth factor (EGF)-induced signal transduction was directly compared with that of glucose and insulin-like growth factor-1 (IGF-1) in INS-1 cells. TGF-/EGF transiently (<20 min) induced phosphorylation of extracellular-regulated kinase (Erk)-1/2 (>20-fold), glycogen synthase kinase (GSK)-3 (>10-fold), and protein kinase B (PKB) (Ser473 and Thr308), but did not increase [3H]thymidine incorporation. In contrast, phosphorylation of Erk1/2, GSK-3, and PKB in response to glucose and IGF-1 was more prolonged (>24 h) and, though not as robust as TGF-/EGF, did increase ß-cell proliferation. Phosphorylation of p70S6K was also increased by IGF-1/glucose, but not by TGF-/EGF, despite upstream PKB activation. It was found that IGF-1 induced phosphatidylinositol 3-kinase (PI3K) association with insulin receptor substrate (IRS)-1 and -2 in a glucose-dependent manner, whereas TGF-/EGF did not. The importance of specific IRS-2-mediated signaling events was emphasized in that adenoviral-mediated overexpression of IRS-2 further increased glucose/IGF-1-induced ß-cell proliferation (more than twofold; P < 0.05) compared with control or adenoviral-mediated IRS-1 overexpressing INS-1 cells. Neither IRS-1 nor IRS-2 overexpression induced a ß-cell proliferative response to TGF-/EGF. Thus, a prolonged activation of Erk1/2 and PI3K signaling pathways is important in committing a ß-cell to a mitogenic event, and it is likely that this sustained activation is instigated by signal transduction occurring specifically through IRS-2.
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