RAP1 MEDIATES SUSTAINED MAP KINASE ACTIVATION-INDUCED BY NERVE GROWTH-FACTOR

Activation of mitogen-activated protein (MAP) kinase (also known as ex tracellular-signal-regulated kinase, or ERK)(1) by growth factors can trigger either cell growth or differentiation. The intracellular signa ls that couple growth factors to MAP kinase may determine the differen t effects of growth factors: for example, transient activation of MAP kinase by epidermal growth factor stimulates proliferation of PC12 cel ls(1), whereas they differentiate in response to nerve growth factor, which acts partly by inducing a sustained activation of MAP kinase(1). Here we show that activation of MAP kinase by nerve growth factor inv olves two distinct pathways: the initial activation of MAP kinase requ ires the small G protein Ras, but its activation is sustained by the s mall G protein Rap1. Rap1 is activated by CRK adaptor proteins and the guanine-nucleotide-exchange factor C3G, and forms a stable complex wi th B-Raf, an activator of MAP kinase. Rap1 is required for at least tw o indices of neuronal differentiation by nerve growth factor: electric al excitability and the induction of neuron-specific genes. We propose that the activation of Rap1 by C3G represents a common mechanism to i nduce sustained activation of the MAP kinase cascade in cells that exp ress B-Raf.