RHEB, A GROWTH FACTOR-REGULATED AND SYNAPTIC ACTIVITY-REGULATED GENE,ENCODES A NOVEL RAS-RELATED PROTEIN

Neuronal activity results in long term cellular changes that underlie normal brain development and synaptic plasticity. To examine the molec ular basis of activity-dependent plasticity, we have used differential cloning techniques to identify genes that are rapidly induced in brai n neurons by synaptic activity. Here we describe an inducible novel me mber of the Ras family of small GTP-binding proteins we have termed Rh eb. rheb mRNA is rapidly and transiently induced in hippocampal granul e cells by seizures and by NMDA-dependent synaptic activity in the lon g term potentiation paradigm. The predicted amino acid sequence of Rhe b is most closely homologous to yeast Ras1 and human Rap2. The putativ e GTP binding regions are highly conserved. A bacterial fusion protein of Rheb binds GTP and exhibits intrinsic GTPase activity. Like Ha-Ras , the carboxyl-terminal sequence encodes a CAAX box that is predicted to signal post-translational farnesylation and to target Rheb to speci fic membranes. rheb mRNA is expressed at comparatively high levels in normal adult cortex as well as a number of peripheral tissues, includi ng lung and intestine. In the developing brain, rheb mRNA is expressed at relatively high levels in embryonic day 19 cortical plate, and exp ression remains at stable levels throughout the remainder of prenatal and postnatal development. Its close homology with ras and its rapid i nducibility by receptor-dependent synaptic activity suggest that rheb may play an important role in long term activity-dependent neuronal re sponses.