Activation of IRS-2-mediated signal transduction by IGF-1, but not TGF-alpha or EGF, augments pancreatic beta-cell proliferation.
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.
Lingohr
Melissa K
MK
Pacific Northwest Research Institute, Seattle, Washington 98122, USA.
Dickson
Lorna M
LM
McCuaig
Jill F
JF
Hugl
Sigrun R
SR
Twardzik
Daniel R
DR
Rhodes
Christopher J
CJ
D000256:Adenoviridae; D000818:Animals; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D004247:DNA / Q000096:biosynthesis; D004815:Epidermal Growth Factor / Q000494:pharmacology*; D005822:Genetic Vectors; D005947:Glucose / Q000494:pharmacology; D055504:Insulin Receptor Substrate Proteins; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology*; D047908:Intracellular Signaling Peptides and Proteins; D007515:Islets of Langerhans / Q000166:cytology / Q000187:drug effects*; D007700:Kinetics; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology*; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010750:Phosphoproteins / Q000235:genetics / Q000502:physiology*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D011972:Receptor, Insulin / Q000502:physiology*; D011994:Recombinant Proteins / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013936:Thymidine / Q000378:metabolism; D014162:Transfection; D016211:Transforming Growth Factor alpha / Q000494:pharmacology*
D055504:Insulin Receptor Substrate Proteins; D047908:Intracellular Signaling Peptides and Proteins; D010750:Phosphoproteins; D011518:Proto-Oncogene Proteins; D011994:Recombinant Proteins; D016211:Transforming Growth Factor alpha; D004815:Epidermal Growth Factor; D007334:Insulin-Like Growth Factor I; D004247:DNA; D011972:Receptor, Insulin; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D005947:Glucose; D013936:Thymidine