ReviewSuppressors of cytokine signalling and regulation of growth hormone action
Introduction
The somatotrophic pathway is a complex series of exquisitely controlled physiological processes that regulate key aspects of growth and metabolism. While a number of the mechanisms by which GH signalling contributes to this process have been well investigated others, in particular the mechanisms by which growth signals are tempered, are only partly understood. Members of the suppressors of cytokine signalling (SOCS) protein family have recently been implicated in regulating cytokine-mediated growth signals. Compelling evidence is emerging that SOCS proteins play important roles in controlling cellular responses to GH.
Section snippets
Signalling by Growth Hormone
Growth hormone (GH) signal transduction shares many of the general characteristics found in a physiologically diverse range of cytokines and growth factors [1]. Cytokines bind to their cognate receptors on the surface of target cells triggering a conformational change in receptor structure and oligomerization. Receptor aggregation allows the recruitment and/or activation of receptor-associated members of the Janus family of kinases (JAKs). The JAKs bind to receptor domains located proximal to
The suppressors of cytokine signalling
The suppressor of cytokine signalling (SOCS) protein family was discovered independently by three groups [7], [8], [9] and consists of eight proteins that share conserved structural and functional domains. The SOCS proteins contain a central SH2 domain, an N-terminal domain of variable length and divergent sequence, and a conserved motif at the C-terminus called the SOCS-Box [10].
In vitro studies have established that, via its SH2 domain, SOCS1 can directly interact with phosphorylated JAK
In vitro actions of SOCS proteins in GH signalling
Soon after the discovery of the SOCS protein family, Adams and colleagues [19] found that CIS, SOCS1, SOCS2 and SOCS3 were all induced in F442A fibroblasts stimulated with GH. Similarly, prominent expression of these SOCS mRNAs was also observed in the liver, lungs and muscle of hypophosectomised rats infused with GH [20]. These observations suggested that SOCS1 and SOCS3 were rapidly induced in response to GH stimulation, but their induction was relatively transient, with transcript levels
Genetic analyses of SOCS function in GH signalling
In vitro analyses have provided key insights into the potential scope and mechanism of SOCS action. They have provided a compelling model that SOCS proteins act to dampen signal transduction through a negative feedback loop initiated by cytokine signalling itself. Thus, it seemed likely that the individual physiological roles of SOCS proteins might be gleaned by defining the cytokine and tissue specificity of SOCS induction. However, it has emerged that multiple SOCS proteins can be induced by
Acknowledgments
The authors’ research is supported by The National Health and Medical Research Council, Canberra, Australia (Program Grant #257500), The National Institute of Health, Bethseda, MD (Grant CA-22556), the Australian Federal Government Cooperative Research Centres Program and AMRAD Operations Pty Ltd. C.J.G. is supported by an Australian Research Council Postgraduate Fellowship.
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