Many G protein coupled receptors (GPCRs) cause phosphorylation of MAP kinases through transactivation of the epidermal growth factor receptor (EGF‐R), leading to increased cell survival and growth, motility, and migration. Phosphoinositide 3‐kinase (PI3K) is one of the important cell survival signaling molecules activated by EGF‐R stimulation. However, the extent to which EGF‐R transactivation is essential for GPCR agonist‐stimulated PI3K activation is not known. Here we examined the mechanism of PI3K activation that elicits GPCR‐mediated ERK1/2 activation by pathways dependent and/or independent of EGF‐R transactivation in specific cell types. Immortalized hypothalamic neurons (GT1‐7 cells) express endogenous gonadotropin‐releasing hormone receptors (GnRH‐R) and their stimulation causes marked phosphorylation of ERK1/2 and Akt (Ser 473) through transactivation of the EGF‐R and recruitment of PI3K. In C9 hepatocytes, agonist activation of AT₁ angiotensin II (AT₁‐R), lysophosphatidic acid (LPA), and EGF receptors caused phosphorylation of Akt through activation of the EGF‐R in a PI3K‐dependent manner. However, ERK1/2 activation by these agonists in these cells was independent of PI3K activation. In contrast, agonist stimulation of HEK 293 cells stably expressing AT₁‐R caused ERK1/2 phosphorylation that was independent of EGF‐R transactivation but required PI3K activation. LPA signaling in these cells showed partial and complete dependence on EGF‐R and PI3K, respectively. These data indicate that GPCR‐induced ERK1/2 phosphorylation is dependent or independent of PI3K in specific cell types, and that the involvement of PI3K during ERK1/2 activation is not dependent solely on agonist‐induced transactivation of the EGF‐R. Published 2005 Wiley‐Liss, Inc.