Growth and migration: Ras in a PI3Kle

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Loss of Ras binding to phosphoinositide 3-kinase γ (PI3Kγ) by mutating its catalytic subunit p110γ leads to diminished Drosophila cell growth and reduced migration of mouse neutrophils.

PI3Ks catalyze the formation of the second messenger lipid phosphatidylinositol (3,4,5) triphosphate (PIP₃), consequently they are are among the most important drivers of cell proliferation and migration. They consist of a regulatory p85 subunit and a catalytic p110 subunit; the small GTPase Ras can bind and activate all PI3K subunits in vitro but the in vivo relevance of this interaction has been unclear. The PI3K subclass PI3Kγ also possesses a distinct regulatory subunit, p101, which participates in PI3Kγ activation by the heterotrimeric G-protein βγ-complex (Gβγ). In Nature Cell Biology, Orme et al. and Suire et al. now show that PI3Kγ requires Ras binding to p110γ for maximum activity.

To investigate the role of Ras in PI3Kγ signaling, both studies used flies and mice expressing mutant forms of p110 subunits that were unable to bind to Ras. Orme et al. looked at the effect of expressing Myc-Dp110&gamma^RBD in flies. Mutant flies had a normal phenotype except for wing size and egg production, which was thought to depend mainly on activation of PI3K through insulin signaling. This study indicates that in Drosophila PI3Kγ activity requires Ras binding in addition to insulin signaling to achieve maximum cell growth and proliferation.

To compare the effect of both Ras and heterotrimeric G-protein binding in the regulation of PI3Kγ activity in mice, Suire et al. used animals expressing p110^DASA/DASA — which can't bind Ras — and animals lacking the p101 regulatory unit (p101^-/-). They found that G-protein activators, known for their effect on PI3Kγ activation, reduced the levels of PIP3 production significantly in both p110^DASA/DASA as well as in p101^-/- neutrophils. Neutrophil migration towards inflammation sites also depends on their capacity to respond to these G-protein activators and the percentage of p110^DASA/DASA neutrophils that were able to move in a chemoattractant gradient was reduced up to 75%. These results reveal an unexpected synergistic effect of Ras and Gβγ binding on PI3Kγ activation. Surprisingly, p110^DASA/DASA — but not p101^-/- neutrophils — were found to have dramatically reduced production of Reactive Oxygen Species (ROS). As ROS is involved in the killing of pathogens by neutrophils this suggests a separation of the downstream effects of PI3K signaling, Ras or Gβγ binding.

The combined results of these two studies show how Ras can modulate PI3K activity in response to specific signaling cascades and in different cellular contexts.

Mirko von Elstermann
Functional Glycomics Gateway

References

Sabine Suire, Alison M. Condliffe, G. John Ferguson, Chris D. Ellson, Hervé Guillou, Keith Davidson, Heidi Welch, John Coadwell, Martin Turner, Edwin R. Chilvers, Phillip T. Hawkins & Len Stephens. Gβγs and the Ras binding domain of p110γ are both important regulators of PI₃K_γ signalling in neutrophils. Nature Cell Biology(15 October 2006) | Article | PubMed |
Mariam H. Orme, Saif Alrubaie, Gemma L. Bradley, Cherryl D. Walker & Sally J. Leevers. Input from Ras is required for maximal PI(₃)K signalling in Drosophila. Nature Cell Biology (15 October 2006); | Article | PubMed |