GH (growth hormone) binding to the GHR (GH receptor) triggers essential signalling pathways that promote growth and metabolic regulation. The sensitivity of the cells to GH is mainly controlled by the endocytosis of the receptor via βTrCP (β-transducin repeat-containing protein). In the present study, we show that βTrCP interacts directly via its WD40 domain with the UbE (ubiquitin-dependent endocytosis) motif in GHR, promoting GHR ubiquitination in vitro. NMR experiments demonstrated that the UbE motif is essentially unstructured, and, together with functional mapping of the UbE and βTrCP WD40 residues necessary for binding, led to a unique interaction model of βTrCP with GHR-UbE. This interaction is different from the conventional βTrCP-substrate interactions described to date. This interaction therefore represents a promising specific target to develop drugs that inhibit GHR endocytosis and increase GH sensitivity in cachexia patients.