Dr. GPCR Virtual Cafe
Abstract
Adhesion G protein-coupled receptors (aGPCRs) are an unusual class of GPCRs with a puzzling diversity of functions in health and disease. They set themselves apart from other GPCRs by their structural and functional diversity and their unique features such as extraordinarily long extracellular N termini comprising various domains. With these special N termini, Adhesion GPCRs display a broad repertoire of ways to mediate cell-cell communication. To do so, Adhesion GPCRs mediate G protein signals into cells (cis signaling) as well as a function completely independent of seven transmembrane domains and C terminus (trans-signaling).
To investigate how Adhesion GPCRs shape cellular communication by this dual mode of signaling, we study Latrophilins as prototypic Adhesion GPCRs, which belong to the oldest members of the receptor class. Using the roundworm Caenorhabditis elegans as a model, we found that the Latrophilin homolog LAT-1 signals via a Gs protein pathway upon activation by a tethered agonistic sequence to coordinate anterior-posterior tissue polarity in the developing embryo. We were able to show that the cis mode coveys a non-polar signal to polarize a cell. Interestingly, while cell polarity is mediated by a classical G protein cascade, LAT-1 also controls cell proliferation solely through its N terminus. This peculiar trans mode is a non-cell-autonomous signal cross-talking with the Notch cascade on the cell membrane.
Both modes seem to be a common feature for several Adhesion GPCR. Their ability to mediate two distinct signals in different biological contexts constitutes a novel signaling principle of this intriguing GPCR class and might be a key in mediating cellular changes.