Conserved role of Ras-GEFs in promoting aging: from yeast to mice

a new article published in the journal Aging, Borras et al. report that Ras-GRF1 homozigous deletion increases both median and maximum longevity in laboratory mice [1]. The human Ras, superfamily now counts more than 150 different proteins subdivided into five different protein families: Ras, Rho, Rab, Arf and Ran. These protein families regulate many cellular processes [2] including cellular differentiation and proliferation (Ras), cell citoskeleton organization and cell shape (Rho), intracellular protein trafficking (Rab, Arf) and nucleo-citoplasmic transport (Ran). Ras protein, the founding member of the small GTP binding protein superfamily, is found mutated in 30% of all human tumors and, in mammals, consists of three genes and four gene products (N-Ras, H-Ras, K-Ras4A and KRas4B). Many of these proteins are ubiquitously expressed but regulated by a multitude of specific Guanine nucleotide Exchange Factors (GEFs) and GTPase Activating Proteins (GAPs). In fact, even though this protein superfamily has the endogenous capability to hydrolyze the bound GTP, GEFs and GAPs, respectively catalyze the activating and the inactivating reactions [3]. It is interesting to note that, although Ras-GRF1 (one of the mammalian GEFs) shows only partial homology to the yeast CDC25 (one of the two yeast GEFs) and mammalian and yeast Ras proteins have limited functional homology, both exchange factors are regulated by the PKA serine/threonine kinase [4, 5] suggesting the existence of conserved Ras-dependent signaling networks. Both RasGRFs were first discovered for their ability to exchange the nucleotide bound to Ras proteins [6, 7] but these multidomain proteins can have additional activities. Commentary Other than the REM and CDC25 domain, capable of exchanging the Ras-bound GDP, full length RasGRFs contain, in fact, a PH domain that can interact with the NGF receptor TrkA [31] and an IQ domain capable of calmodulin binding and responsible for calcium modulation [8; 9]. It also contains a second PH-DH domain that is capable of binding to membrane bound PI(4,5)P2, microtubules [10], phosphatidic acid, Rho and Rac GTPase [11, 12, 5] and spinophilin, a scaffold protein that interact with actin filaments and p70 S6 kinase [13]. It is therefore possible that the RasGRF1-/-mouse phenotype may be due to the impairment of GTP binding proteins other than Ras or to inhibition of other signaling cascades. However, it must be noted that Ras-GRF1 signaling is required for normal beta cell development and glucose homeostasis and that isolated islet from GRF1 knockout fail to activate Akt and Erk [14] …