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.
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.
Cousin
S P
SP
Department of Internal Medicine, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75235-8854, USA.
Hügl
S R
SR
Myers
M G
MG
White
M F
MF
Reifel-Miller
A
A
Rhodes
C J
CJ
D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D000818:Animals; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000378:metabolism*; D051380:GRB2 Adaptor Protein; D005947:Glucose / Q000378:metabolism*; D013006:Growth Hormone / Q000494:pharmacology*; D055504:Insulin Receptor Substrate Proteins; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins; D007515:Islets of Langerhans / Q000187:drug effects* / Q000378:metabolism; D053614:Janus Kinase 2; D008894:Milk Proteins; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D011506:Proteins / Q000378:metabolism; D011518:Proto-Oncogene Proteins; D051381:Rats; D019893:Ribosomal Protein S6 Kinases / Q000378:metabolism; D050799:STAT5 Transcription Factor; D055765:Shc Signaling Adaptor Proteins; D015398:Signal Transduction; D020839:Son of Sevenless Protein, Drosophila / Q000378:metabolism; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D015534:Trans-Activators / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D004268:DNA-Binding Proteins; D051380:GRB2 Adaptor Protein; C495950:Grb2 protein, rat; D055504:Insulin Receptor Substrate Proteins; D047908:Intracellular Signaling Peptides and Proteins; C526296:Irs1 protein, rat; C526299:Irs2 protein, rat; D008894:Milk Proteins; D010750:Phosphoproteins; D011506:Proteins; D011518:Proto-Oncogene Proteins; D050799:STAT5 Transcription Factor; D055765:Shc Signaling Adaptor Proteins; C528035:Shc1 protein, rat; D020839:Son of Sevenless Protein, Drosophila; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D015534:Trans-Activators; D007334:Insulin-Like Growth Factor I; D013006:Growth Hormone; D011505:Protein-Tyrosine Kinases; C507927:Jak2 protein, rat; D053614:Janus Kinase 2; D019893:Ribosomal Protein S6 Kinases; D020928:Mitogen-Activated Protein Kinases; D005947:Glucose