Stimulation of pancreatic beta-cell proliferation by growth hormone is glucose-dependent: signal transduction via janus kinase 2 (JAK2)/signal transducer and activator of transcription 5 (STAT5) with no crosstalk to insulin receptor substrate-mediated mitogenic signalling

• Published in: Biochemical journal Vol. 344 Pt 3; no. 3; pp. 649 - 658
• Main Authors: Cousin, S P, Hügl, S R, Myers, Jr, M G, White, M F, Reifel-Miller, A, Rhodes, C J
• Format: Journal Article
• Language: English
• Published: England 15.12.1999
• Subjects: Adaptor Proteins, Signal Transducing; Adaptor Proteins, Vesicular Transport; Animals; Cell Division - drug effects; Cell Line; DNA-Binding Proteins - metabolism; Glucose - metabolism; GRB2 Adaptor Protein; Growth Hormone - pharmacology; Insulin Receptor Substrate Proteins; Insulin-Like Growth Factor I - metabolism; Intracellular Signaling Peptides and Proteins; Islets of Langerhans - drug effects; Islets of Langerhans - metabolism; Janus Kinase 2; Milk Proteins; Mitogen-Activated Protein Kinases - metabolism; Phosphoproteins - metabolism; Phosphorylation - drug effects; Protein-Tyrosine Kinases - metabolism; Proteins - metabolism; Proto-Oncogene Proteins; Rats; Ribosomal Protein S6 Kinases - metabolism; Shc Signaling Adaptor Proteins; Signal Transduction; Son of Sevenless Protein, Drosophila - metabolism; Src Homology 2 Domain-Containing, Transforming Protein 1; STAT5 Transcription Factor; Trans-Activators - metabolism
• ISSN: 0264-6021; 1470-8728
• DOI: 10.1042/0264-6021:3440649

Mitogenic signal-transduction pathways have not been well defined in pancreatic beta-cells. In the glucose-sensitive rat beta-cell line, INS-1, glucose (6-18 mM) increased INS-1 cell proliferation (>20-fold at 15 mM glucose). Rat growth hormone (rGH) also induced INS-1 cell proliferation, but this was glucose-dependent in the physiologically relevant concentration range (6-18 mM glucose). The combination of rGH (10 nM) and glucose (15 mM) was synergistic, maximally increasing INS-1 cell proliferation by >50-fold. Moreover, glucose-dependent rGH-induced INS-1 cell proliferation was increased further by addition of insulin-like growth factor 1 (IGF-1; 10 nM) to >90-fold at 12 mM glucose. Glucose metabolism and phosphatidylinositol-3'-kinase (PI3'K) activation were necessary for both glucose- and rGH-stimulated INS-1 cell proliferation. Glucose (>3 mM) independently increased tyrosine-phosphorylation-mediated recruitment of growth-factor-bound protein 2 (Grb2)/murine sons of sevenless-1 protein (mSOS) and PI3'K to insulin receptor substrate (IRS)-1 and IRS-2, as well as SH2-containing protein (Shc) association with Grb2/mSOS and downstream activation of mitogen-activated protein kinase and 70 kDa S6 kinase. Glucose-induced IRS- and Shc-mediated signal transduction was enhanced further by the addition of IGF-1, but not rGH. In contrast, rGH was able to activate Janus kinase 2 (JAK2)/signal transducer and activator of transcription 5 (STAT5) signal transduction at glucose concentrations above 3 mM, but neither glucose independently, nor glucose with added IGF-1, were able to activate the JAK2/STAT5 signalling pathway. Thus rGH-mediated proliferation of beta-cells is directly via the JAK2/STAT5 pathway without engaging the Shc or IRS signal-transduction pathways, although activation of PI3'K may play an important permissive role in the glucose-dependent aspect of rGH-induced beta-cell mitogensis. The additive effect of rGH and IGF-1 on glucose-dependent beta-cell proliferation is therefore reflective of rGH and IGF-1 activating distinctly different mitogenic signalling pathways in beta-cells with minimal crosstalk between them.