25 years of Ras structural biochemistry: interaction and network perspectives

Signal transduction of Ras and Ras-like proteins is regulated by three classes of canonical interacting partners. These include regulators that control activation of the GTPase cycle (by guanine nucleotide exchange factors, GEFs), its inactivation (by GTPase-activating proteins, GAPs), and a wide spectrum of effectors (e.g. Raf kinase and PI3 kinase) that initiate signaling cascades downstream of Ras and Ras-like proteins. Currently, it has become more evident that an increasing number of additional Ras binding partners are critical in modulating and integrating Ras in various signaling networks at biological membranes. However, the roles of these additional Ras interaction proteins as novel modulators of Ras signaling remain unclear. We consider that these control elements safeguard the strength, efficiency and specificity of Ras-dependent signal transduction and provide an attractive new generation of highly selective drug targets that attenuate rather than inhibit Ras signaling. Preliminary results on deciphering new functional control mechanisms of Ras signal transduction will be discussed.