Linda Van Aelst

Research

My research is focused on signal transduction pathways involving members of the Ras and Rho GTPases and the physiological processes they regulate. These proteins play key roles in cellular activities controlling cellgrowth control, differentiation and morphogenesis. Alterations that affect normal Ras and Rho function result inthe development of several diseases including cancer and neuropathologies. Our efforts are centered on defining therole and mechanisms by which Ras and Rho family members exert their effectson tumorigenesis and on neuronal development and associated disorders, including mental retardation and autism.

We have utilized several model systems to gain insights into the roles of these GTPases and their regulators and effectors. For example, using Drosophila, wedemonstrated a role for Rap1 and its effector Canoe/AF-6 in the regulation of epithelial cell shape changes and cell adhesion, pivotal events governing tumor progression and wound healing processes. Using knockout mice we provided evidence for a role of the Ras-GAP associated protein, Dok-1, in the negative regulation of mitogenic and p210bcr-abl signaling and leukemogenesis. Our studies have also provided insights into how perturbations in Ras and hosignaling canimpact neuronal development and function.  For instance, we found that Ras and Rap GTPases play indispensable roles in activity dependent synaptic plasticity. Furthermore, we demonstrated key roles for Rho regulators in the genesis and polarization of neurons.  Finally, my lab showed that oligophrenin-1, a Rho-GAP involved in X-linked mental retardation, is required for activity-dependent maturation and plasticity of synapses.