H-, K- and N-Ras represent the prototype members of a family of small G proteins which are frequently activated to an oncogenic state in a wide variety of human tumors. Activation is due to point mutations at position 12 or 61 within their coding sequence. Such mutations cause these proteins to be constitutively converted to their active GTP-bound rather than the inactive GDP-bound state. The related human R-Ras gene was initially cloned by low stringency hybridization methods. Position 38 or 87 mutants of R-Ras (analogous to positions 12 and 61 in H-Ras) have been shown to be capable of activating oncogenic function. Ras p21 in its active GTP binding state binds to Raf-1, resulting in activation of the MAP kinase signaling cascade. An additional member of the Ras family, Rheb (Ras-related GTP-binding protein), also interacts with Raf-1. This interaction is potentiated by growth factors and agents that increase cAMP levels.