Growth Hormone Receptor Interacting Proteins

Abstract

Growth hormone (GH) promotes muscle strength, fights infections, accelerates wound healing and accelerates recovery after bone fractures. In addition, children with delayed growth can be treated with GH. Recently, the growth hormone receptor has also been implicated in cancer growth. Therefore, understanding how cells regulate the activity of GH is very important. Most cells of the body have GH receptors. The sensitivity of cells for GH depends both at its concentration in the blood and on the number of GH receptors at the cell surface. After synthesis GH receptors stay only 30-60 minutes at the cell surface. They disappear via two mechanisms: a protease from the outside cuts the growth hormone binding domain from the receptor, while a ubiquitin system-dependent internalization event directs the remaining receptors to endosomes and lysosomes for degradation. In her thesis, Julia Schantl identified and characterized novel proteins that regulate both processes. The findings were based on identification by mass spectrometry of proteins that interact with the Ubiquitin-dependent Endocytosis (UbE) motif of the receptor in a pulldown assay using the F345A mutated UbE motif as control. She identified Small glutamine-rich tetratricopeptide-containing protein alpha (SGTA), a TPR domain containing protein, which interacted through the first TPR motif with the UbE motif. This interaction was independent of the ubiquitin system, indicating that the ubiquitin system acts downstream of the GH receptor-SGTA interaction. A second very interesting protein was Large proline-rich protein Bag6 (Scythe). This protein contains a ubiquitin-like domain at its N-terminus and binds through its C-terminal Bag6 domain to Hsc70. Originally identified as an anti-apoptotic protein, she localized the protein to mitochondria, the nucleus, and peri-nuclear area. Most likely Bag6 acts together with GSTA in GH receptor dimerization, and multimerization at the endoplasmic reticulum and in the Golgi complex. The third protein identified was large proline rich protein 130 kDa (LRP130). Chapter IV shows that GHR directly interacts with its sheddase, TACE (Adam17), which is responsible for the proteolytic release of the GH binding protein. She showed that interaction still occurred in the presence of GH, a condition under which shedding by TACE is inhibited.