Negative regulation by proteasomal degradation of receptor tyrosine kinase ErbB3

University Of California At Davis, Davis CA

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Abstract

DESCRIPTION (provided by applicant): The primary objective of this project is to describe the regulatory systems of cellular growth in order to provide a foundation for cancer therapeutics and drug development. This goal well reflects the mission of the NCI as the resolution of this project would provide fundamental knowledge of a cellular system as a means to gain insight to the development of novel treatments for cancer and thereby reducing the burdens of disease on the state. The focus of this project will be on growth factor receptor tyrosine kinases (RTK) whose dysregulation contributes to solid tumor initiation, growth, and progression in an immense number and variety of cancer types (1-3). Treatments for these cancers are often designed to stem or retard the functionality of RTKs as in the case of ErbB2, an RTK overexpressed in 25% of breast cancers, where receptor activity is curtailed with trastuzumab (Herceptin), a humanized monoclonal antibody specific to ErbB2 (4). However, in recent years it has emerged that the overexpression of ErbB3, an RTK of the same family, contributes to the growth and progression of ErbB2-positive breast tumors, as well as to therapeutic resistance, a major barrier in breast cancer treatment (5), thus leading to a need of describing the regulatory mechanisms that restrict ErbB3 levels in normal (non-transformed) mammary epithelial cells. Studies in our lab strongly suggest that normal (non-transformed) mammary epithelial cells employ potent post-transcriptional negative regulatory mechanisms that restrict ErbB3 levels, while tumor cells inactivate these mechanisms to promote their growth and malignancy (6,7). Post-transcriptional negative regulation of RTKs often occurs through the lysosome-mediated degradation of receptors that have been internalized from the cell surface (8,9). However, our lab has recently discovered that cells suppress ErbB3 levels via the degradation of newly synthesized receptors at the endoplasmic reticulum (ER); extraneous receptors are targeted to the proteasome via their ubiquitination (10). This project will explore this novel type of regulatin of ErbB3 at the endoplasmic reticulum. Mechanisms of this control mechanism will be elucidated including the protein components that are involved in the targeting, ubiquitination, and retrotranslocation of ErbB3 to the cytosol for 26S proteasome-dependent degradation. This project is intended to be carried out using techniques in biochemistry, cell, and molecular biology including mammalian tissue culture, immunoprecipitation, western blotting, microscopy, and molecular cloning. The project will be supplemented by regular attendance of scientific presentations on topics in cancer research, biochemistry, and molecular biology that would be at all relevant to the subject matter and approaches outlined above. Furthermore, courses related to the project would aid in the development of perspectives and strategies important to the progression of the technical and theoretical facets of the research.