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 have revealed that these GH-regulated, male-specific phenotypes are a direct consequence of GH pulse-dependent STAT5b activation and that loss of function of STAT5b cannot be compensated for by the closely related signalling molecule STAT5a. Physiological plasma GH pulses are required to obtain the high levels of activated STAT5b seen in the livers of males, and down-regulation of the GH receptor (GHR)-JAK-STAT5b pathway in hepatocytes exposed to GH in a near-continuous fashion underlies the low level of liver STAT5b activity that is characteristic of adult female rats. Termination of nuclear STAT5b 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, which block the further activation of STAT5b by binding to and inhibiting the action of the GHR-JAK2 complex via multiple mechanisms. In this manner, the liver cell is rendered temporarily unresponsive to further GH-signalling events. SOCS-CIS proteins synthesized in liver cells stimulated continuously with GH may also contribute to the apparent down-regulation of STAT5b signalling that is observed in the female rat liver.
Choi
H K
HK
Department of Biology, Boston University, Massachusetts 02215, USA.
Waxman
D J
DJ
D000818:Animals; D001835:Body Weight; D002352:Carrier Proteins / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D015536:Down-Regulation; D005260:Female; D005786:Gene Expression Regulation; D013006:Growth Hormone / Q000097:blood / Q000502:physiology*; D017874:Immediate-Early Proteins / Q000378:metabolism; D053614:Janus Kinase 2; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D010641:Phenotype; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D011505:Protein-Tyrosine Kinases / Q000502:physiology*; D011518:Proto-Oncogene Proteins; D051381:Rats; D011986:Receptors, Somatotropin / Q000378:metabolism; D012097:Repressor Proteins; D012737:Sex Factors; D015398:Signal Transduction; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D014158:Transcription, Genetic; D014443:Tyrosine / Q000378:metabolism
D002352:Carrier Proteins; D013006:Growth Hormone; D017874:Immediate-Early Proteins; D053614:Janus Kinase 2; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D011518:Proto-Oncogene Proteins; D011986:Receptors, Somatotropin; D012097:Repressor Proteins; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D014443:Tyrosine; C491590:Socs1 protein, mouse; C491589:Socs1 protein, rat; C106612:Stat5b serine kinase; C507926:Jak2 protein, mouse; C507927:Jak2 protein, rat