Signal transduction is the fundamental biological process of converting changes in extracellular information into changes in intracellular functions. It controls a wide range of cellular activities, from the release of neurotransmitters and hormones, to integrated cellular decisions of proliferation, differentiation, survival, or death. The vast majority of extracellular signaling molecules exert their cellular effects through activation of G protein-coupled receptors (GPCRs); however, the G-protein coupled paradigm is by no means the exclusive mechanism of membrane receptor signal transduction. Polypeptide ligands such as nerve growth factor act exclusively on receptor tyrosine kinase receptors (RTKs) to promote signaling. GPCRs and RTKs both form an interface between extracellular and intracellular physiology by converting hormonal signals into changes in intracellular metabolism and ultimately cell phenotype. Initially, it was thought that GPCRs and RTKs represented linear and distinct signaling pathways that converge on downstream targets to regulate cell division and gene transcription. However, activation of second messenger generating systems do not fully explain the range of effects of GPCR or RTK activation on biological processes such as differentiation and cell growth. Recent work has revealed that GPCR and RTK signaling pathways are not mutually exclusive of one another; in fact, they often function as partners, forming complex signaling networks through scaffold/nexus proteins.

The work described herein examines the complexity of signal regulation by multifunctional nexus proteins. I showed that the activation of phospholipase C-ϵ by Gα_12/13-coupled receptors occurs through a mechanism involving the small GTPase Rho. I demonstrated the usefulness and complexities of 'regulators of G-protein signaling' (RGS proteins) for discerning the Gα selectivity of GPCR signaling. Finally, I found that RGS12, in addition to regulating Gα signaling, acts as a Ras/Raf/MEK scaffold in nerve growth factor-mediated differentiation. The work presented here expands our understanding of how multiple domain proteins facilitate convergence and cross-regulation of RTK, heterotrimeric G-protein, and Ras-superfamily signaling.