Endocrine Abstracts

Growth hormone (GH) signals through the GH receptor (GHR), a member of the cytokine receptor superfamily. The extracellular domain of the GHR exists as a soluble form known as the GH binding protein (GHBP). The GHBP is either derived from the GHR by proteolysis (man, rabbit) or from the GHR gene by alternative splicing (rodents). The GHBP circulates in blood and modulates GH action by i) altering GH kinetics, ii) competing with GHRs for ligand, and iii) unproductive GHR/GHBP heterodimer formation. Furthermore, GHR proteolysis acts a mechanism for GHR depletion/downregulation from the cell surface. Recently, the protease responsible for GHR cleavage/GHBP generation has been tentatively identified as TACE (TNF-alpha converting enzyme), a metalloproteinase also known as ADAM 17. Specific inhibitors of this class of proteases decrease GHR cleavage and GHBP shedding. GHR-containing cells derived from TACE knockout animals fail to produce GHBP, but regain GHBP shedding capacity when transfected with TACE. TACE is expressed in many tissues, and preliminary experiments suggest that in humans GHBP is generated in multiple tissues. TACE activity appears to be regulated by a protein kinase C-dependent pathway, and GHBP shedding can be stimulated by phorbol esters. The precise cleavage point for TACE proteolysis is unknown, but a conformational rather than linear GHR epitope may be required. The GHR-dimer induced by GH binding is less prone to proteolysis than are GHR monomers, thereby allowing GH signalling as well as internalization of the GH-GHR complex. The modulation of GH action by the metalloproteinase TACE thus has complex consequences that encompass both positive (enhancer) and negative (inhibitor) activities for GH action.