Endocrine Abstracts

The growth hormone (GH) receptor is a key regulator of cellular metabolism. Using model cell systems we have investigated how GH-induced signaling is regulated, both in paracrine and autocrine conditions.

Three features render GHR unique: (a) an active ubiquitination system is required for both endocytosis and degradation in lysosomes; (b) uptake of receptor is a continuous process, independent of GH binding and Jak2 signal transduction; (c) only cell surface expression of dimerised GHRs is controlled by the ubiquitin system. Despite recent progress, molecular mechanisms underlying GHR endocytosis and degradation are unknown. Evidence from research on the interferon and prolactin receptors has identified SCF^TrCP as a positive factor for their degradation. This E3 is known for its regulatory role in cell division and various signal transduction pathways. Our results show that the ubiquitin ligase SCF^TrCP is required for GHR endocytosis: removal of its mRNA by small interference RNA results in inhibition of GH uptake. In addition, we demonstrate that interaction between GHR and beta-TrCP is independent of a canonical DSGxxS motif. These results show the involvement of a SCF E3 ligase in endocytosis, thereby regulating GH-sensitivity of cells. In cells that produce both GH and GHR, the situation is basically the same. In these cells we investigated how GH affects GHR receptor degradation, and how the Jak/Stat signaling pathway is regulated. The consequences of these studies are important for understanding autocrine-activated GHR in fetal and peri-natal, and cancer tissues.