Agonists for a subset of G‐protein coupled receptors (GPCRs), including thrombin, S1P and LPA, elicit receptor coupling to G12/13 family proteins which stimulate exchange factors to activate RhoA. We have explored novel downstream signals by which RhoA links GPCRs to cell growth. One pathway involves RhoA mediated transactivation of the matricellular protein Cyr61/CCN1. CCN1 is secreted from the cell and signals through integrins. We have shown that CCN1 signaling through α5β1 integrins is required for thrombin induced proliferation of 1321N1 glioblastoma cells. Integrin signaling is also regulated from inside‐out through activation of another small G‐protein, Rap1. Thrombin signaling to RhoA leads to sustained activation of Rap1 and increases cell adhesion and integrin signaling through Rap1, suggesting that GPCRs also engage integrin mediated pathways from within the cell. Rap1 also plays a central role in GPCR mediated glioblastoma proliferation both in vitro and in vivo. Rap1a siRNA treatment significantly attenuates thrombin stimulated DNA synthesis in two glioblastoma cell lines. Furthermore lentiviral shRNA to Rap1a markedly inhibits growth of both cell lines in a mouse xenograft model. We are currently exploring the role of GPCR signaling through RhoA, Rap1 and integrins in glioblastoma tumor cell growth in vivo.