Identification of Neuropilin-plexin hetero-oligomerization domains

The semaphorins are a large family of extracellular signaling molecules that induce a wide diversity of cellular outcomes throughout development, including cell adhesion, cell migration, tissue patterning, cell proliferation, viability, and changes in the cytoskeleton. Dysregulation of semaphorin signaling has been strongly linked to a number of diseases, including lung cancer and CHARGE syndrome, as well as an etiological factor in congenital heart defects. Semaphorins bind directly to a family of type I transmembrane co-receptors, the plexins (plex) and neuropilins (nrp), in order to transduce signals across cell membranes. Although it is known that plexins and neuropilins oligomerize at the cell surface, the stoichiometry of the co-receptor complex formed upon semaphorin binding, and how changes in co-receptor oligomeric state alter transmembrane signal transduction, are unclear.

 

The goals of this project are twofold:

 

(1) determine if receptor composition mediates distinct downstream cellular outcomes using a heterologous system,

(2) to define the domains of the receptor and co-receptors responsible for heterooligomerization.

 

Completion of the aims of this proposal will provide insights into how distinct intracellular signaling events are initiated by a common signal (i.e. Sema3d) and will reveal important biophysical properties that regulate receptor heterooligomerization during signal transduction.