Signal transduction mechanisms underlying growth hormone receptor action

Our understanding of the mechanisms of action of GH and its receptor, the GHR, has advanced significantly in the last decade and has provided some important surprises. It is now clear that the GH-GHR axis activates a number of inter-related signalling pathways, not all of which are dependent on the intracellular tyrosine kinase, JAK2 as originally postulated. JAK2-independent pathways, mediated via the Src family kinases, together with a number of negative regulators of GH signalling and emerging cross-talk mechanisms with other growth factor receptors, provide a complex array of mechanisms that are capable of fine-tuning responses to GH in a cell context dependent manner. Additionally, it is also now clear that GH and the GHR can translocate to the nucleus of target cells and initiate, as yet not well defined, nuclear responses. Continued emphasis on elucidation of these complex mechanisms is critical to provide further insights into the diverse physiological and pathophysiological effects of GH.