NERVE GROWTH-FACTOR ACTIVATES EXTRACELLULAR SIGNAL-REGULATED KINASE AND P38 MITOGEN-ACTIVATED PROTEIN-KINASE PATHWAYS TO STIMULATE CREB SERINE-133 PHOSPHORYLATION

The mechanisms by which growth factor-induced signals are propagated t o the nucleus, leading to the activation of the transcription faster C REEP, have been characterized, Nerve growth factor (NGF) was found to activate multiple signaling pathways that mediate the phosphorylation of CREB at the critical regulatory site, serine 133 (Ser-133). NGF act ivates the extracellular signal-regulated kinase (ERK) mitogen-activat ed protein kinases (MAPKs), which in turn activate the pp90 ribosomal S6 kinase (RSK) family of Ser/Thr kinases, all three members of which were found to catalyse CREB Ser-133 phosphorylation in vitro and in vi vo, In addition to the ERK/RSK pathway, we found that NGF activated th e p38 MAPK and its downstream effector, MAPK-activated protein kinase 2 (MAPKAP kinase 2), resulting in phosphorylation of CREB at Ser-133, Inhibition of either the ERK/RSK or the p38/MAPKAP kinase 2 pathway on ly partially blocked NGF-induced CREB Ser-133 phosphorylation, suggest ing that either pathway alone is sufficient for coupling the NGF signa l to CREB activation. However, inhibition of both the ERK/RSK and the p38/MAPKAP kinase 2 pathways completely abolished NGF-induced CREB Ser -133 phosphorylation. These findings indicate that NGF activates two d istinct MAPK pathways, both of which contribute to the phosphorylation of the transcription factor CREB and the activation of immediate-earl y genes.