Ras-Erk-ETS Signaling as an Effector of the IIS Longevity Response

Fontana et al., 2010 Fontana L.

Partridge L.

Longo V.D. Extending healthy life span—from yeast to humans. Kenyon, 2011 Kenyon C. The first long-lived mutants: discovery of the insulin/IGF-1 pathway for ageing. Bonafè et al., 2003 Bonafè M.

Barbieri M.

Marchegiani F.

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Giampieri C.

Mugianesi E.

Centurelli M.

Franceschi C.

Paolisso G. Polymorphic variants of insulin-like growth factor I (IGF-I) receptor and phosphoinositide 3-kinase genes affect IGF-I plasma levels and human longevity: cues for an evolutionarily conserved mechanism of life span control. Kuningas et al., 2007 Kuningas M.

Mägi R.

Westendorp R.G.

Slagboom P.E.

Remm M.

van Heemst D. Haplotypes in the human Foxo1a and Foxo3a genes; impact on disease and mortality at old age. Suh et al., 2008 Suh Y.

Atzmon G.

Cho M.O.

Hwang D.

Liu B.

Leahy D.J.

Barzilai N.

Cohen P. Functionally significant insulin-like growth factor I receptor mutations in centenarians. The key role of IIS in determining animal lifespan has been well appreciated for more than two decades and shows strong evolutionary conservation (). Alleles of genes encoding components of this pathway have also been linked to longevity in humans (). Multiple studies have demonstrated the importance of the PI3K-Akt-Foxo branch of IIS, while in this study we identify an equally important role for Ras-Erk-ETS signaling in IIS-dependent lifespan extension.

Orme et al., 2006 Orme M.H.

Alrubaie S.

Bradley G.L.

Walker C.D.

Leevers S.J. Input from Ras is required for maximal PI(3)K signalling in Drosophila. Oldham et al., 2002 Oldham S.

Stocker H.

Laffargue M.

Wittwer F.

Wymann M.

Hafen E. The Drosophila insulin/IGF receptor controls growth and size by modulating PtdInsP(3) levels. We have shown that, downstream of chico, preventing the activation of either Ras or PI3K is sufficient to extend lifespan. Ras can interact directly with the catalytic subunit of PI3K, which is required for maximal PI3K activation during growth (). Thus, inhibition of Ras could increase lifespan via inactivation of PI3K. However, several lines of evidence indicate that the Erk-ETS pathway must also, if not solely, be involved. In this study and elsewhere, we demonstrated that direct inhibition of the Ras-dependent kinase, Erk, or activation of the Aop transcription factor, a negative effector of the Ras-Erk pathway, is sufficient to extend lifespan. Importantly, we show that Ras-Erk-ETS signaling is genetically linked to chico because activation of Aop is required for lifespan extension due to chico loss of function. Furthermore, altering the ability of Chico to activate Ras or PI3K does not result in equivalent phenotypes: we and others () showed that mutation of the Grb2/Drk docking site in Chico is dispensable for multiple developmental phenotypes associated with chico mutation, while disruption of the Chico-PI3K interaction is not. Overall, our observations strongly suggest that lifespan extension downstream of chico mutation involves inhibition of the Ras-Erk-ETS-signaling pathway.

Alic et al., 2014 Alic N.

Giannakou M.E.

Papatheodorou I.

Hoddinott M.P.

Andrews T.D.

Bolukbasi E.

Partridge L. Interplay of dFOXO and two ETS-family transcription factors determines lifespan in Drosophila melanogaster. Alic et al., 2014 Alic N.

Giannakou M.E.

Papatheodorou I.

Hoddinott M.P.

Andrews T.D.

Bolukbasi E.

Partridge L. Interplay of dFOXO and two ETS-family transcription factors determines lifespan in Drosophila melanogaster. Figure 6 Model of Aop-Foxo Function Downstream of IIS Show full caption We propose that, downstream of the insulin receptor substrate, Chico, signaling via the IIS pathway bifurcates into two branches: Ras-Erk and PI3K-Akt. At the transcriptional level, these two branches subsequently re-join, acting on the Aop and Foxo TFs in a non-additive manner. The two TFs then co-operatively regulate the expression of a subset of target genes required for lifespan extension. The simplest model to integrate the role of Ras-Erk-ETS signaling with the PI3K-Akt-Foxo branch in extension of lifespan by reduced IIS is presented in Figure 6 . We propose that, downstream of Chico, the IIS pathway bifurcates into branches delineated by Erk and Akt, with inhibition of either sufficient to extend lifespan, as is activation of either responsive TF, Aop or Foxo. The two branches are not redundant, because mutation of chico or the loss of its ability to activate either branch results in the same magnitude of lifespan extension. Furthermore, Aop and Foxo are each individually required downstream of chico mutation for lifespan extension. At the same time, the effects of the two branches are not additive, as simultaneous activation of Aop and Foxo does not extend lifespan more than activation of either TF alone (). Taken together, these data suggest that the two pathways re-join for transcriptional regulation, where Aop and Foxo co-operatively regulate genes required for lifespan extension. Our model is corroborated by our previous finding that, in the adult gut and fat body, some 60% of genomic locations bound by Foxo overlap with regions of activated-Aop binding (). We propose that functional interactions of Aop and Foxo at these sites may be such that each factor is both necessary and sufficient to achieve the beneficial changes in target gene expression upon reduced IIS.

Alic et al., 2011 Alic N.

Andrews T.D.

Giannakou M.E.

Papatheodorou I.

Slack C.

Hoddinott M.P.

Cochemé H.M.

Schuster E.F.

Thornton J.M.

Partridge L. Genome-wide dFOXO targets and topology of the transcriptomic response to stress and insulin signalling. Alic et al., 2014 Alic N.

Giannakou M.E.

Papatheodorou I.

Hoddinott M.P.

Andrews T.D.

Bolukbasi E.

Partridge L. Interplay of dFOXO and two ETS-family transcription factors determines lifespan in Drosophila melanogaster. Teleman et al., 2008 Teleman A.A.

Hietakangas V.

Sayadian A.C.

Cohen S.M. Nutritional control of protein biosynthetic capacity by insulin via Myc in Drosophila. Wu et al., 2013 Wu J.

Lee S.W.

Zhang X.

Han F.

Kwan S.Y.

Yuan X.

Yang W.L.

Jeong Y.S.

Rezaeian A.H.

Gao Y.

et al. Foxo3a transcription factor is a negative regulator of Skp2 and Skp2 SCF complex. Yang et al., 2014 Yang Y.C.

Tang Y.A.

Shieh J.M.

Lin R.K.

Hsu H.S.

Wang Y.C. DNMT3B overexpression by deregulation of FOXO3a-mediated transcription repression and MDM2 overexpression in lung cancer. It remains to be determined how promoter-based Foxo and Aop interactions produce such physiologically relevant, transcriptional changes. It is, however, curious that activation of either TF alone promotes longevity when one is known as a transcriptional activator (Foxo) and the other as a transcriptional repressor (Aop). We have consistently observed a subset of Foxo-bound genes, albeit a minority, that are transcriptionally repressed when Foxo is activated (). Furthermore, the Foxo target gene myc is downregulated in larval muscle when Foxo is active under low insulin conditions, while deletion of foxo or its binding site within the myc promoter results in de-repression of myc expression in adipose of fed larvae (). Thus, on some promoters under certain conditions, Drosophila Foxo appears to act as a transcriptional repressor. Mammalian Foxo3a may also directly repress some genes (). It will therefore be important to test whether the lifespan-relevant interactions between Foxo and Aop occur on promoters where Foxo acts as a repressor with Foxo possibly acting as a cofactor for Aop or vice versa.