GROWTH HORMONE’S INTRACELLULAR SIGNALING: CURRENT VIEW, PHYSIOLOGICAL EFFECTS, FORWARDLOOKING ASSESSEMENT

Abstract

The growth hormone (GH), although most well known for regulating linear growth, has a great number of another important biological functions like controlling physiological processes related to the cardiovascular, hepatobiliary, renal, gastrointestinal, and reproductive systems. Despite intensive studies during the past decade, the exact molecular mechanisms of Jak activation have largely remained controversial. It is evident that much more detailed structural information regarding Jaks and the Jakcytokine-receptor complex is needed to enhance our understanding of the mechanism of Jak activation. A substantial number of key class I cytokine receptors utilize Janus kinase 2 (JAK2) for signalling. The growth hormone (GH) and erythropoietin (EPO) receptors were the first of these to be discussed, and later the prolactin, interleukins 3, 5 and 6, (GM-CSF), interferon-γ (IFNγ), thrombopoietin (TPO) and leptin receptors were found to recruit this ubiquitous tyrosine kinase. Therefore, the growth hormone activates the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) signaling pathway, and recent studies have provided a new understanding of the mechanism of JAK2 activation by growth hormone binding to its receptor. The spectrum of physiological processes regulated by JAK2 is therefore vast, ranging from postnatal growth, reproduction and lactation through the regulation of metabolism and body composition, bone formation. JAK2 activation is required for growth hormone-mediated activation of STAT1, STAT3, and STAT5, and the negative regulation of JAK–STAT signaling comprises an important step in the control of this signaling pathway. The GHR also activates the Src family kinase signaling pathway independent of JAK2 , also able to trigger the mitogen-activated protein kinase (MAPK) pathways. Also, the exact mechanism and functional relevance of autophosphorylation at different sites in Jaks is not known but will be an interesting area for future research. Another important topic for future studies is to define the mechanisms of crosstalk between Jaks and other pathways. Therefore, this review covers the molecular mechanisms of GHR activation and signal transduction as well as the physiological consequences of growth hormone signaling.

Keywords

• growth hormone
• growth hormone receptor
• janus kinase 2
• insulin-like growth factor 1.