RGS proteins (regulators of G protein signaling) are a diverse family of proteins that act to negatively regulate signaling by heterotrimeric G proteins. Initially characterized as GTPase-activating proteins for Galpha subunits, recent data have implied additional functions for RGS proteins. We previously identified an RGS protein (termed RGSZ1) whose expression is quite specific to neuronal tissue (Glick, J. L., Meigs, T. E., Miron, A., and Casey, P. J. (1998) J. Biol. Chem. 273, 26008-26013). In a continuing effort to understand the role of RGSZ1 in cellular signaling, the yeast two-hybrid system was employed to identify potential effector proteins of RGSZ1. The microtubule-destabilizing protein SCG10 (superior cervical ganglia, neural specific 10) was found to directly interact with RGSZ1 in the yeast system, and this interaction was further verified using direct binding assays. Treatment of PC12 cells with nerve growth factor resulted in Golgi-specific distribution of SCG10. A green fluorescent protein-tagged variant of RGSZ1 translocated to the Golgi complex upon treatment of PC12 cells with nerve growth factor, providing evidence that RGSZ1 and SCG10 interact in cells as well as in vitro. Analysis of in vitro microtubule polymerization/depolymerization showed that binding of RGSZ1 to SCG10 effectively blocked the ability of SCG10 to induce microtubule disassembly as determined by both turbidimetric and microscopy-based assays. These results identify a novel connection between RGS proteins and the cytoskeletal network that points to a broader role than previously envisioned for RGS proteins in regulating biological processes.