Signaling mechanism for the insulin-like effects of growth hormone--another example of a classical hormonal negative feedback loop.
Growth hormone (GH) exerts many effects in addition to its ability to stimulate growth. The metabolic effects are either chronic diabetogenic or acute insulin-like. The latter effects are only seen in cells that have been deprived of the hormone for a few hours. After exposure to GH the ability of the cells to respond with insulin-like effects disappears within a couple of hours, a negative feedback loop, which is a part of the chronic effects of the hormone. The insulin-like effects are mediated by the cytosolic tyrosine kinase Janus kinase 2 (JAK2) upon GH-GH receptor interaction, resulting in tyrosine phosphorylation of downstream targets including the GH receptor itself and insulin receptor substrate-1 (IRS-1) and IRS-2. Analogous to the post-receptor events for insulin this results in recruitment of phosphatidylinositol-3 kinase (PI3-kinase) to the IRS-proteins. Downstream PI3-kinase protein kinase B/Akt participates in the activation of glucose transporters (GLUT4) and increased glucose uptake as well as activation of phosphodiesterase 3B and hydrolysis of cAMP leading to a net dephosphorylation of the hormone sensitive lipase and inhibition of lipolysis. Simultaneously, JAK2 phosphorylates STAT-family transcription factors that move into the nucleus and activate the transcription of, among others, genes coding for negatively regulatory proteins called Suppressors of cytokine signalling (SOCS). The turnover of SOCS is rapid and in their presence JAK2 will still activate STAT-proteins (and the diabetogenic effects), but no longer phosphorylate the IRS-proteins (and induce insulin-like effects), closing the loop of yet another classical hormonal negative feedback loop.
Ridderstråle
Martin
M
Department of Endocrinology, Lund University, University Hospital MAS, S-205 02 Malmö, Sweden. martin.ridderstrale@endo.mas.lu.se
D000818:Animals; D025461:Feedback, Physiological / Q000502:physiology*; D013006:Growth Hormone / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D015398:Signal Transduction / Q000502:physiology*; D013002:Somatomedins / Q000737:chemistry / Q000378:metabolism*
D013002:Somatomedins; D013006:Growth Hormone