The ubiquitin-proteasome pathway and the regulation of growth hormone receptor availability

The number of growth hormone receptors (GHR) per cell are regulated and this feature plays a major role in the hormone responsiveness of the body. This article deals with the regulatory mechanisms underlying the availability of GHR for serum growth hormone. The availability of membrane proteins at the cell surface can be regulated at different locations within the cell: (1) The amount of protein synthesized in the endoplasmic reticulum (ER) is largely controlled by gene transcription. In addition, the ER quality control system regulates the exiting of properly folded proteins from the ER. (2) In the trans-Golgi network, proteins can either be diverted directly to the lysosomes or be transported to the cell surface. (3) At the plasma membrane, the endocytic machinery can select proteins for endocytosis via clathrin-coated pits or proteins may be subject to proteolysis, resulting in shedding of the extracellular domain. (4) In endosomes, internalized proteins are either recycled back to the plasma membrane or targeted to the lysosome for degradation. At each of these cellular locations the ubiquitin-proteasome pathway can specifically regulate protein levels via different mechanisms. In transfected Chinese hamster lung cells, GHR availability is determined by three factors: endocytosis (75%), shedding (10%), and other undetermined mechanisms (15%). As outlined in this article the level of GHR at the cell surface, defined as GHR availability, is mainly regulated by the ubiquitin-proteasome pathway.