Hepatocyte growth factor stimulates proliferation of pancreatic beta-cells particularly in the presence of subphysiological glucose concentrations

Abstract

We investigated the role of hepatocyte growth factor (HGF) in β-cell growth and its complex intracellular signal transduction pathways. Cell proliferation was measured in the β-cell line INS-1 using [ 3 H]thymidine incorporation. Activation of mitogenic signaling proteins was assessed using co-immunoprecipitation, immunoblot analysis and specific protein activity inhibitors in proliferation assays. HGF (1·375 nM) increased INS-1 cell proliferation in the presence of 3-24 mM glucose up to 45-fold vs unstimulated controls. HGF exceeded the effect of glucose alone (2·2-fold at 3 mM glucose and 1·7-fold in the presence of 15 mM glucose). The HGF-induced INS-1 cell proliferation was further increased by addition of IGF-I or GH. Stimulation with HGF activated the JAK-2/STAT-5 pathway with a subsequent activation of phosphatidylinositol-3′-kinase (PI3′K). PI3′K activation was necessary for HGF-and glucosestimulated INS-1 cell proliferation. The effect of PI3′K was mediated via 70 kDa S6 kinase and protein kinase B, which showed maximum activation in the presence of 3-6 mM glucose. Protein kinase C was essential for HGF-induced INS-1 cell proliferation. The HGF effect was also mediated at low glucose concentrations via insulin receptor substrate 4 (IRS-4) whereas other IRS proteins did not show any activation. High glucose concentrations also showed an increased IRS-4/PI3′K binding and therefore activation. In conclusion, β-cell proliferation is mediated via complex interacting signal transduction pathways. HGF, in contrast to other growth factors, seems to be of importance particularly in the presence of low glucose concentrations and therefore takes a special role in this complex concert.

JAK-STAT pathway in carcinogenesis: Is it relevant to cholangiocarcinoma progression?

“…STAT3 activation has been shown to be necessary for full biological responses of HGF and HGF induced proliferation [115][116][117] . In hepatocytes and some other cell types HGF activates the STAT3 signaling pathway, moreover, not only STAT3 but also STAT1α/STAT1β and STAT5 interact with c-Met [118,119] . STAT3 phosphorylation induced by HGF/c-Met signaling is limited by consequent positive HGF action on SOCS3 expression in some cell types.…”

Gene Transfer of Constitutively Active Akt Markedly Improves Human Islet Transplant Outcomes in Diabetic Severe Combined Immunodeficient Mice

“…Glucose and growth factors such as glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), IGF-I, or hepatocyte growth factor (HGF) have been shown to increase the phosphorylation/activation of Akt in insulinoma cells and mouse islets (11,(13)(14)(15)(16)(17)(18). Blockade of PI3K-Akt pathway in pancreatic ␤-cells has been shown to blunt proliferative and/or prosurvival effects induced by GLP-1, GIP, IGF-I, HGF, or glucose in these cells (11,(13)(14)(15)(16)(17)(18).…”

The acquisition of an insulin-secreting phenotype by HGF-treated rat pancreatic ductal cells (ARIP) is associated with the development of susceptibility to cytokine-induced apoptosis

“…In the present study, we demonstrated that treatment of pancreatic ductal cells with HGF promoted their differentiation into insulinsecreting cells. Such an ability of HGF to promote beta-cell terminal differentiation extends the spectrum of activities of this growth factor, previously shown to induce in vivo and in vitro differentiation of beta cells (Otonkoski et al 1994a,b, 1996, García-Ocaña et al 2000, Gahr et al 2002. HGF has also been shown to increase in vitro the expression of Reg, a protein implicated in pancreatic regeneration (Anastasi et al 1999, Kobayashi et al 2000, and to convert, when administered alone or in combination with activin A, pancreatic acinar AR42J cells into insulin-producing cells (Mashima et al 1996).…”