The biochemistry and molecular cell physiology of the Ras-related small GTP binding proteins, Rit and Rin

The Ras super family of small guanine nucleotide binding proteins (GTPases) acts as molecular switches to control a wide variety of cellular events. These proteins can be grouped according to both homology and function to give six subfamilies that regulate cellular functions such as cellular proliferation and differentiation (Ras family), vesicular trafficking (Rab and Arf families), organization of the cytoskeleton (Rho family), nuclear transport (Ran family) and ion-channel regulation (Rem/Rad/Gem family). Recently two novel small GTPases, Rit and Rin were discovered and belong to the Ras subfamily. Thus, it is likely that Rit and Rin are involved in proliferation and differentiation regulation in a manner that is similar to Ras, but may impinge on distinct or novel signal transduction pathways.; Rit (R&barbelow;as i&barbelow;n all t&barbelow;issues) and Rin (Ras in neurons) are both highly expressed in the nervous system. Interestingly, Rin is the only small GTPase to be exclusive to the nervous system. We began to elucidate the function of Rit and Rin by using neuronal model cells and primary neuronal cultures. The activation of Rin is mediated by receptor tyrosine kinase ligands, such as nerve growth factor (NGF) and epidermal growth factor (EGF). Constitutively-active Ras potently stimulated Rin while dominant-negative Ras inhibited NGF mediated Rin activation suggesting that Rin is a down stream target of the NGF/TrkA/Ras signaling cascade. The importance of Rin function was demonstrated by dominant-negative Rin's ability to inhibit neuronal differentiation of PC6 cells as mediated by Ras and NGF. However, Rin was not sufficient to induce neuronal differentiation on its own.; Rit was demonstrated to be both sufficient and necessary for induction of neuronal differentiation in PC6 cells. Rit could protect neuronal cells from cell death invoked by both serum starvation and toxins. The ability of Rit to activate extra-cellular regulated kinase (ERK) was indispensable in its ability to promote differentiation and survival. Although, NGF and Ras could stimulate Rit activity it was unclear if Rit was a direct target of these pathways.