Many G protein-coupled receptors (GPCRs) are known to modulate cell growth and differentiation by stimulating the extracellular signal-regulated protein kinases (ERKs). In growth factor signaling, ERKs are typically stimulated through an elaborate network of modules consisting of adaptors, protein kinases, and the small GTPase Ras. The mechanism by which G protein signals tap into the ERK signaling pathway has thus far remain elusive. Members of the G family of G proteins, in particular Gα, have been shown to associate with tetratricopeptide repeat 1 (TPR1), an adaptor protein which preferentially binds to Ras. Here, we examined if TPR1 is indeed the missing link between Gα signaling and Ras activation. Expression of GαQL, a constitutively active mutant of Gα, in HEK 293 cells led to the formation of GTP-bound Ras and the subsequent phosphorylation of ERK. Likewise, stimulation of endogenou G-coupled CCR1 chemokine receptors produced the same responses in human erythroleukemia cells. siRNA-mediated knockdown of TPR1 or expression of a dominant negative mutant of TPR1 effectively abolished the ability of GαQL to induce Ras activation in HEK 293 cells. In contrast, these manipulations had no inhibitory effect on GαQL-induced activation of phospholipase Cβ. GαQL-induced phosphorylations of downstream targets including ERK, signal transducer and activator of transcription 3, and IκB kinase were significantly suppressed upon expression of the dominant negative mutant of TPR1. Furthermore, SOS2, a Ras guanine nucleotide exchange factor, was found to form a complex with TPR1 and GαQL. Expression of SOS2 enhanced GαQL-induced Ras activation and its subsequent signaling. Collectively, our results suggest that Gα regulates multiple signaling pathways by activating Ras through its association with TPR1, but TPR1 is not required for Gα to stimulate phospholipase Cβ. © 2010 Elsevier Inc.