Growth hormone receptor signalling and actions in bone growth

Growth hormone (GH) acts by binding to a membrane receptor that is part of the cytokine receptor superfamily. Ligand binding induces receptor dimerization leading to activation of the associated tyrosine kinase, Janus kinase (Jak) 2. Transphosphorylation of Jak2 occurs followed by tyrosine phosphorylation of the receptor, and numerous cytoplasmic proteins. Among these are the signal transducers and activators of transcription (Stat) proteins, as well as adaptor proteins leading to the activation of the Ras/mitogen-activated protein (MAP) kinase and the phosphatidyl-inositol-3'-kinase (PI 3-kinase) pathways. Activation of the GH receptor system is relatively transient, with several mechanisms being involved in down-regulation: internalization and degradation of the receptor and recruitment of phosphatases or specific inhibitors of the Jak-Stat pathway, the suppressors of cytokine signalling (SOCS) proteins. Finally, the use of the GH receptor knock-out mouse model has allowed us to dissect the role of this hormone in post-natal body growth and homeostasis.