The RGS protein Crg2 links the mating and cAMP signal transduction pathways in C. neoformans. The pheromone-responsive mating pathway is regulated by the pheromone receptor Ste3α, heterotrimeric G-protein Gpa2/Gpb1/Gpg1/2, and the RGS protein Crg1. The G-protein-coupled receptor homolog Gpr4, Gpa1/Gib2/Gpg1/Gpg2, and Crg2 govern the conserved cAMP signaling pathway to regulate differentiation and the production of virulence factors. The Gα protein Gpa3 mediates a distinct signaling pathway in mating that is negatively regulated by both Crg1 and Crg2. Both the mating and cAMP signaling pathways are important for fungal virulence. MFa/α, mating type a or α; MAPK, mitogen-activated protein kinase.