From Ras to PI3K

Abstract

The catalytic p110 subunits of class 1 phosphoinositide 3-kinases (PI3Ks) have a conserved Ras binding domain (RBD), and an interaction has been noted between Ras guanosine triphosphatase (GTPase) and p110 PI3K in vitro and in overexpression systems. However, the biological relevance of this putative regulatory input has been unclear. Two groups now report a physiological role for Ras interactions with PI3K in flies and mouse neutrophils. Orme et al . created transgenic flies carrying a Dp110 (the only Drosophila p110) with mutations in the RBD that did not interact with Ras (either Ras1 or Ras2) but was otherwise biochemically normal. This Dp110 RBD rescued flies from lethal deletion of Dp110 ; however, the rescued flies were smaller and females exhibited reduced fecundity, laying 60% fewer eggs. Dp110 RBD flies also had decreased activation of Akt in response to insulin in the brain and imaginal discs and decreased basal Akt activation in the ovaries. Although the interaction with Ras does not appear essential for PI3K signaling, it does appear to maximize the response. The authors suggest that different developmental contexts may require different levels of signaling. In this case, egg production, which requires massive growth, is one process with the highest dependency on the intensity of the PI3K signal. In mammals there are multiple isoforms of PI3K, and Suire et al . showed that the p110γ isoform, which is stimulated by G protein-coupled receptors through the action of Gβγ and an adaptor (in neutrophils the adaptor is p101), also appeared to be activated by Ras. They compared the neutrophil responsiveness to chemotactic agents fMLP or C5a, which are G protein-coupled receptor ligands, in cells isolated from mice in which p101 was knocked out to prevent Gβγ activation of p110γ or in which the RBD of p110γ was mutated (p110γ DASAA ) to prevent Ras activation. For cells carrying either mutation, production of phosphoinositide (3,4) diphosphate or phosphoinositide (3,4,5) triphosphate, activation of Akt, and chemotaxis were decreased compared with wild-type cells or cells from mice heterozygous for p110γ. In vivo, recruitment of neutrophils in response to peritonitis was diminished in the mutant mice. The production of reactive oxygen species in response to agonist stimulation showed selectivity in that only the cells from the p110γ DASAA mice exhibited a reduction in this arm of the PI3K pathway, suggesting that one role of Ras may be to activate a separate pool of PI3K from that activated by Gβγ. These two articles provide examples in which Ras may control the intensity of the PI3K signal in one context and provide selectivity to the signaling process in another. M. H. Orme, S. Alrubaie, G. L. Bradley, C. D. Walker, S. J. Leevers, Input from Ras is required for maximal PI(3)K signalling in Drosophila . Nat. Cell Biol. 8 , 1298-1302 (2006). [PubMed] S. Suire, A. M. Condliffe, G. J. Ferguson, C. D. Ellson, H. Guillou, K. Davidson, H. Welch, J. Coadwell, M. Turner, E. R. Chilvers, P. T. Hawkins, L. Stephens, Gβγs and the Ras binding domain of p110γ are both important regulators of PI(3)Kγ signalling in neutrophils. Nat. Cell. Biol. 8 , 1303-1309 (2006). [PubMed]