Activation of IRS-2-mediated signal transduction by IGF-1, but not TGF-alpha or EGF, augments pancreatic beta-cell proliferation.
| Autor: | Lingohr, Melissa K, Dickson, Lorna M, McCuaig, Jill F, Hugl, Sigrun R, Twardzik, Daniel R, Rhodes, Christopher J |
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| Předmět: |
PROTEIN metabolism
CELL receptors ANIMAL experimentation CARRIER proteins CELL division CELL lines CELLULAR signal transduction COMPARATIVE studies DNA DYNAMICS EPIDERMAL growth factor GENES GENETIC techniques GLUCOSE GROWTH factors ISLANDS of Langerhans RESEARCH methodology MEDICAL cooperation PHOSPHOPROTEINS PHOSPHORYLATION RECOMBINANT proteins RESEARCH SOMATOMEDIN TRANSFERASES VIRUSES EVALUATION research SIGNAL peptides DEOXYRIBONUCLEOSIDES CELL physiology |
| Zdroj: | Diabetes; Apr2002, Vol. 51 Issue 4, p966-976, 11p |
| Abstrakt: | Transforming growth factor (TGF)-alpha- 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-alpha/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) (Ser(473) and Thr(308)), but did not increase [(3)H]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-alpha/EGF, did increase beta-cell proliferation. Phosphorylation of p70(S6K) was also increased by IGF-1/glucose, but not by TGF-alpha/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-alpha/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 beta-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 beta-cell proliferative response to TGF-alpha/EGF. Thus, a prolonged activation of Erk1/2 and PI3K signaling pathways is important in committing a beta-cell to a mitogenic event, and it is likely that this sustained activation is instigated by signal transduction occurring specifically through IRS-2. [ABSTRACT FROM AUTHOR] |
| Databáze: | Complementary Index |
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