Seminar

Trimeric G protein signaling beyond GPCRs: teaching new tricks to an old dog

Mikel García-Marcos, PhD

Dysregulation of trimeric G protein signaling is the cause of major diseases that represent a huge burden for public health such as cancer, cardiovascular diseases, neurological malfunction, inflammation or metabolic disorders, among others. In the classical model, G protein-coupled receptors (GPCRs) are the Guanine nucleotide Exchange Factors (GEFs) that activate trimeric G proteins. Noteworthy, >30% of currently marketed drugs target GPCRs. However, our recent work has led to the identification of an alternative mechanism of G protein activation that does not require GPCRs, thereby providing a new perspective on the functioning and targeting of this pathway. We have discovered a new family of non-receptor GEFs which is structurally defined by the presence of a conserved sequence motif. Members of this new family of GEFs assemble alternative G protein signaling circuits in cells and play important roles in cancer progression towards metastasis or in Wnt-mediated developmental pathways in vertebrates.