Tyrosine phosphorylation of the growth hormone (GH) receptor and Janus tyrosine kinase-2 is involved in the insulin-like actions of GH in primary rat adipocytes.

Abstract

The nature of tyrosine phosphorylations induced by GH in relation to the insulin-like metabolic effects in primary rat adipocytes was investigated. Unlike other cells, e.g. 3T3-F442A fibroblast, in which GH is believed to initiate cell differentiation through activation of the Janus tyrosine kinase-2 (JAK2), the adipocytes are metabolically active and fully differentiated cells that do not proliferate. Thus, it cannot be assumed that the same molecular mechanisms relay the acute insulin-like effects of GH. In adipocytes responsive to these effects, we found that GH induced tyrosine phosphorylation of a 114-kilodalton membrane protein, identified as the GH receptor, and a 130-kilodalton cytosolic protein, identified as JAK2. In contrast, these phosphorylations were not seen in adipocytes refractory to these effects of GH. The GH concentration dependency (ED50,1-2 nM) of these phosphorylations coincided with the increase in lipogenesis and the decrease in noradrenaline-induced lipolysis caused by the hormone. In analogy with the effects of insulin, the onset of phosphorylation was rapid (t1/2, < 1 min) and preceded the metabolic responses. The observations that a small fraction of the receptor pool became tyrosine phosphorylated and that the level of phosphorylation induced by GH decreased at higher GH concentrations agree with the concept that GH-induced dimerization of the receptor is necessary for signal transduction. We conclude that tyrosine phosphorylation of JAK2 and the GH receptor seems to be involved in the signal transduction mechanism leading to the insulin-like effects of GH in adipocytes. Importantly, the signal pathways for GH and insulin clearly differ at the receptor level, but seem to converge at or before the level of insulin receptor substrate 1 or 2 phosphorylation that has been shown to occur in response to both of these hormones.