In most target cells, activation of the type 1 corticotropin-releasing hormone (CRH) receptor (CRH-R1) by CRH or urocortin (UCN I) leads to stimulation of the Gs-protein/adenylyl cyclase/PKA cascade. Signal transduction of CRH-R1 also involves alternative pathways such as phosphorylation of extracellular signal-regulated kinase (ERK1/2) and p38 mitogen activated protein kinase (MAPK), two members of the MAPK family that mediate important pathophysiological responses. The intracellular pathways by which CRH-R1 activates these MAPK are only partially understood; here we characterized further, signaling mechanisms and molecules involved in CRH-R1-mediated ERK1/2 and p38 MAPK activation. In HEK293 cells overexpressing recombinant CRH-R1, UCN I induced ERK1/2 and p38 MAPK activation was dependent on signaling molecules involved in agonist-induced CRH-R1 trafficking and endocytosis. Furthermore, time course studies and use of selective inhibitors demonstrated that ERK1/2 activation occured within 5min, was sustained for at least 60min and was dependent on both PI3-K/Akt activation and epidermoid growth factor receptor (EGF-R) transactivation involving matrix metelloproteinases (MMPs). UCN I effect on p38 MAPK phosphorylation was more transient, returned to basal within 40min and was dependent on EGF-R transactivation, but not PI3-K/Akt activation. Overexpression of G_-transducin, showed that G_-subunits activation is only partially required for ERK1/2 phosphorylation and does not play a role in p38 MAPK phosphorylation, whereas overexpression of a dominant negative Ras (Ras N17) attenuated both ERK and p38 MAPK activation. In conclusion, a complex signaling network appears to mediate CRH-R1-MAPK interactions; PI-3K might play a critical role in the regulation of CRH-R1 signaling selectivity and cellular responses.