Elizabeth Bruce Professor of Cancer Research, Eppley Institute
Courtesy Appointment - Department of Biochemistry and Molecular Biology
Director of the Center for Breast Cancer Research
Tel: 402-559-8572 (Office)
Molecular Control of Tyrosine Kinase Signaling: Cell Biology and translation
Summary of Research:
The major focus of our laboratory is to define the role of ubiquitin-dependent endocytic traffic of tyrosine kinase-coupled cell surface receptors in regulating cell signaling in epithelial cells and lymphocytes. In addition, we focus on the role of these pathways in cancer cell signaling with the goal of developing and refining targeted therapeutics in cancer.
A major direction in the laboratory is to define the role of Cbl-family proteins, initially identified as proto-oncogene products, as negative regulators of signals initiated by tyrosine kinase-coupled cell surface receptors. We and others have defined the role of Cbl proteins as activated tyrosine kinase-directed ubiquitin ligases (E3s). The targets of Cbl-mediated regulation in lymphocytes include Syk/ZAP70 tyrosine kinases as well as members of the Src-family kinases. Cbl E3s have also emerged as key regulators of ubiquitin-dependent endocytic sorting of receptor tyrosine kinases, providing a critical negative regulatory control for receptors involved in numerous physiological functions and disease states such as cancer. Our current work addresses the nature of the biochemical and cell biological machinery involved in tyrosine kinase regulation by Cbl E3s with a focus on ErbB and PDGF receptors. Given the importance of controlling the intensity of a tyrosine kinase coupled receptors to ensure an appropriate level of cellular activity, and the dramatic consequences of aberrant tyrosine kinase activity, our basic studies carry far-reaching implications for understanding and possibly manipulating a number of pathological entities. For example, ways to enhance Cbl recruitment to receptors or elevation of Cbl protein levels may aid in controlling autoimmune diseases while inhibitors of Cbl function may prove useful in enhancing immune responses and could help control serious infections and improve the efficiency of vaccines. ErbB2, a major participant in the pathogenesis of breast and other epithelial cancers, is relatively resistant to Cbl-mediated negative regulation. Therefore, we have investigated if other ubiquitin ligases could downregulate ErbB2. These studies have led to the identification of a molecular chaperone-associated ubiquitin ligase CHIP as a mediator of ErbB2 downregulation upon HSP90 inhibition. As HSP90 inhibitors are now in clinical development as anticancer agents, these studies provide a strong translational potential for breast cancer therapy. In particular, our laboratory is investigating the possibility of combining CHIP and Cbl ubiquitin ligase pathways for potentiation of anti-ErbB2 therapy.
Activated receptor tyrosine kinases that are not sorted to lysosomes continue to signal intracellularly and are eventually recycled to the cell surface for repeated cycles of signaling. This is a pattern seen with ErbB2 and accounts for its signaling superiority and higher oncogenic potential. Therefore, we are investigating the nature of intracellular signals that emanate from internalized ErbB receptors and the nature of molecular machinery that controls the duration of their intracellular transit and final recycling. These studies focus on the role of Src-family tyrosine kinases, which are known to collaborate with ErbB receptors and on a new family of recycling endocytic proteins with EH domains – the EHD protein family. These basic studies are aimed at understanding a fundamental cellular process and at translating these lessons into clinical practice to develop agents that could help in the control of autoimmune diseases or serve as targeted therapies against cancer.