The general interest of our lab is to understand mechanisms for regulation of signaling proteins through intra- and inter-molecular interactions. Specificity, we focus on receptor-mediated signaling pathways involved in neuron development and axonal guidance, such as the semaphoring/plexin and the NGF/Trk receptor tyrosine kinase pathways, including the receptors themselves and downstream targets and regulatory proteins. We use a combination of biochemical, X-ray crystallographic and cell biological approaches to seek an understanding of the regulatory mechanisms at the atomic level.
A better understanding of the regulatory mechanisms for players in these complicated signaling systems will not only have implications on how cells respond properly to various inputs through precisely controlled protein machineries in general, but also help develop new therapies for related diseases such as neurodegenerative disorder and cancer.
Current Focus: Regulation and signaling mechanisms of the axon guidance receptors plexins. We have recently shown that the plexin intracellular region has GTPase activating protein (GAP) activity specific to the Ras homolog Rap, and this activity is critical for its signaling. Our latest crystal structures elucidate how dimerization allosterically drives activation of the RapGAP domain of plexin, which then catalyzes GTP hydrolysis for Rap by using a non-canonical mechanism.