Kodi S. Ravichandran, BVSc, PhD
Intracellular signaling pathways in hematopoietic cells and their regulation of growth and differentiation
The long-term goal of Ravichandran laboratory is to understand the intracellular signaling pathways in hematopoietic cells and how they regulate outcomes such as cell growth/differentiation. Two of the current projects in the lab (one directly related to cancer and two that are indirectly related) have greatly benefited from being a member of the UVA Cancer Center. The first project involves understanding the role of the adapter protein Shc in T cell development. The Shc adapter protein is a proto-oncogene and its expression and tyrosine phosphorylation are often upregulated in several cancer cell lines. Using transgenic mice conditionally expressing dominant negative Shc as well as conditional knockout mice that ablate Shc expression in T cells, they have ascribed a key role for Shc in T cell development and have gained insights about Shc mediated growth regulation. These studies were done in close collaboration with Dr. Timothy P. Bender at the University of Virginia (also a UVA Cancer Center member). The second project involves the molecular understanding of clearance of apoptotic cells in vivo. The proper disposal of the apoptotic cell corpses play a critical role in preventing chronic inflammation and predisposition to cancer, and could also affect clearance of tumor cells after chemotherapies and anti-tumor immune responses to these tumors. The lab has identified a novel signaling pathway involving ELMO1 and Dock180 proteins, which regulate engulfment as well as cell migration. Dock180/ELMO complex function as an activator of the small GTPase Rac. Interestingly, Rac-mediated cytoskeletal changes has been linked to tumor metastasis in several cases and recently, a member of the Dock180 family (DOCK4) was identified in a screen for genes regulating tumor metastasis. They are addressing the function of ELMO and Dock180 proteins through the use of cell lines, as well as mice knocked out for specific genes.