General description:
Our major aim is to elucidate the molecular mechanisms that determine the Growth Hormone (GH) sensitivity of cells. Cells of the human body contain GH receptors (GHR). Upon GH binding these receptors initiate signal transduction that results in the expression of genes involved in anabolic processes such as protein synthesis, lipid degradation. The GHR regulates body size, increases lean body mass, decreases body fat, and stimulates the immune system. In stress, the cells rapidly lose their GH receptors, probably due to increased activity of the ubiquitin system. Stress implies cancer/aids, severe burning/uraemia, and old age. Recently, we identified the RING E3 SCF(TrCP) as an important factor in GHR endocytosis. Ultimately, our research must lead to drugs that increase the GH sensitivity of cells and reverse the cachectic situation caused by disease.
Role in RUBICON:
The group will characterize the protein networks involved in GHR trafficking and degradation, using pull-down procedures, mass spec analysis, siRNA techniques, and live-cell imaging. In addition, we will use inhibitors of ubiquitination, endocytosis and proteasomal activity to elucidate role and composition of the networks at several key regulatory points in the degradation of the GHR. Ubiquitin ligases and de-ubiquitinating enzymes (DUBs) will be identified and tested for their involvement in GHR trafficking and degradation. From the protein networks we will also isolate and analyse ubiquitinated proteins to investigate the targets of the E3 ligase. SiRNA techniques and mutational analysis will be used to determine their roles in GHR degradation. We expect that the E3 ligase is the primary controlling factor. Based on current evidence, we will develop screens to find drugs able to control GH-sensitivity.
Collaborations: on E3 function: Aaron Ciechanover; on neddylation: Melchior, Hay, Jentsch, Gordon, Genschik; on identification of small molecules: DDF, on TrCP-GHR crystallography: Titia Sixma.
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