Pulsatility of growth hormone (GH) signalling in liver cells: role of the JAK-STAT5b pathway in GH action

The intracellular signalling molecule and transcriptional activator STAT5b is a key mediator of the effects of intermittent plasma growth hormone (GH) pulses on the male-specific pattern of liver gene expression and pubertal body growth rates in rodents, Experiments with Stat5b gene-knockout mice ha ve revealed that these GH-regulated, male-specific phenotypes are a direct consequence of GH pulse-dependent STAT5b activation and that loss of functi on of STAT5b cannot be compensated for by the closely related signalling mo lecule STAT5a. Physiological plasma GH pulses are required to obtain the hi gh levels of activated STAT5b seen in the livers of males, and down-regulat ion of the GH receptor (GHR)-JAK-STAT5b pathway in hepatocytes exposed to G H in a near-continuous fashion underlies the low level of liver STAT5b acti vity that is characteristic of adult female rats. Termination of nuclear ST AT5b signalling occurs at the conclusion of a plasma GH pulse, with STAT5b deactivation catalysed by a tyrosine phosphatase. In males, termination of the intracellular signalling stimulated by a plasma GH pulse is proposed to be additionally facilitated by GH-STAT5b-inducible SOCS-CIS proteins, whic h block the further activation of STAT5b by binding to and inhibiting the a ction of the GHR-JAK2 complex via multiple mechanisms. In this manner, the liver cell is rendered temporarily unresponsive to further GH-signalling ev ents. SOCS-CIS proteins synthesized in liver cells stimulated continuously with GH may also contribute to the apparent down-regulation of STAT5b signa lling that is observed in the female rat liver. (C) 2000 Harcourt Publisher s Ltd.