Input from Ras is required for maximal PI(3)K signalling in Drosophila

Orme, Mariam; Alrubaie, Saif; Bradley, Gemma L.; Walker, Cherryl D.; Leevers, Sally J.

doi:10.1038/ncb1493

Cited by 60 publications

(57 citation statements)

References 25 publications

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“…These findings are supported by evidence demonstrating that input from Ras is required for maximal p110g and Drosophila p110 signaling (Orme et al, 2006;Suire et al, 2006). For the oncogenic activity of p110a in mice, binding to Ras has Figure 9 PI3K isoform-selective inhibitors affect signaling downstream of their desired target isoform.…”

Section: Discussionmentioning

confidence: 82%

Oncogenic signaling of class I PI3K isoforms

et al. 2007

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The catalytic subunits of class I PI3Ks comprise four isoforms: p110a, p110b, p110d and p110c. Cancer-specific gain-of-function mutations in p110a have been identified in various malignancies. Cancer-specific mutations in the non-a isoforms of class I PI3K have not yet been identified, however overexpression of either wild-type p110b, p110c or p110d is sufficient to induce cellular transformation in chicken embryo fibroblasts. The mechanism whereby these non-a isoforms of class I mediate oncogenic signals is unknown. Here we show that potently transforming class I isoforms signal via Akt/mTOR, inhibit GSK3b and cause degradation of FoxO1. A functional Erk pathway is required for p110c and p110b transformation but not for transformation by p110d or the H1047R mutant of p110a. Transformation and signaling by p110c and p110b are sensitive to loss of interaction with Ras, which acts as a membrane anchor. Mutations in the C2 domain of p110d reduce transformation, most likely by interfering with membrane association. Several small molecule inhibitors potently and specifically inhibit the oncogenic signaling and transformation of each of the class I PI3K, and, when used in combination with MEK inhibitors, can additively reduce the transformation induced by p110b and p110c.

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Section: Discussionmentioning

confidence: 82%

Oncogenic signaling of class I PI3K isoforms

et al. 2007

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“…The activated tyrosine-phosphorylated insulin receptor phosphorylates IRS, which in turn activates PI3K, eventually leading to Glut4 translocation and glucose uptake. While IRS-1 is particularly important for insulin-stimulated PI3K activity and Glut4 translocation in adipose cells (49), Ras signaling also plays a prominent role in activation of PI3K (50,51) and glucose uptake (52). Therefore, the roles of insulin and Ras signaling were determined in Ad-36 -induced PI3K activation.…”

Section: Discussionmentioning

confidence: 99%

Metabolically Favorable Remodeling of Human Adipose Tissue by Human Adenovirus Type 36

et al. 2008

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OBJECTIVE-Experimental infection of rats with human adenovirus type 36 (Ad-36) promotes adipogenesis and improves insulin sensitivity in a manner reminiscent of the pharmacologic effect of thiozolinediones. To exploit the potential of the viral proteins as a therapeutic target for treating insulin resistance, this study investigated the ability of Ad-36 to induce metabolically favorable changes in human adipose tissue. RESEARCH DESIGN AND METHODS-We determinedwhether Ad-36 increases glucose uptake in human adipose tissue explants. Cell-signaling pathways targeted by Ad-36 to increase glucose uptake were determined in the explants and human adipose-derived stem cells. Ad-2, a nonadipogenic human adenovirus, was used as a negative control. As a proof of concept, nondiabetic and diabetic subjects were screened for the presence of Ad-36 antibodies to ascertain if natural Ad-36 infection predicted improved glycemic control.RESULTS-Ad-36 increased glucose uptake by adipose tissue explants obtained from nondiabetic and diabetic subjects. Without insulin stimulation, Ad-36 upregulated expressions of several proadipogenic genes, adiponectin, and fatty acid synthase and reduced the expression of inflammatory cytokine macrophage chemoattractant protein-1 in a phosphotidylinositol 3-kinase (PI3K)-dependent manner. In turn, the activation of PI3K by Ad-36 was independent of insulin receptor signaling but dependent on Ras signaling recruited by Ad-36. Ad-2 was nonadipogenic and did not increase glucose uptake. Natural Ad-36 infection in nondiabetic and diabetic subjects was associated with significantly lower fasting glucose levels and A1C, respectively. CONCLUSIONS-Ad-36 proteins may provide novel therapeutic targets that remodel human adipose tissue to a more metabolically favorable profile.

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“…Whether Ras is involved in this process is unknown. However, the recent findings that Ras is required for maximal PI3K signaling in Drosophila (Orme et al, 2006), that it directly binds to and activates PI3K␥ in neutrophils (Suire et al, 2006), and that it is required for PtdIns(3,4,5)P 3 and lamellipodium production in adenocarcinoma cells (Yip et al, 2007) support a universal role for Ras in the regulation of PI3K function. Although the activation of the Ras-PI3K circuit is apparently stochastic in vegetative Dictyostelium cells and promotes random motility in the absence of an extracellular stimulus, chemotactic signaling probably induces a biased localized activation of the Ras-PI3K circuit, thereby restricting it to the leading edge of migrating cells and allowing them to move directionally.…”

Section: Chemotaxis In the Absence Of Pi3k And/or Ptenmentioning

confidence: 99%

The regulation of cell motility and chemotaxis by phospholipid signaling

Kölsch

Charest

Firtel

2008

Journal of Cell Science

320

315

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Phosphoinositide 3-kinase (PI3K), PTEN and localized phosphatidylinositol (3,4,5)-trisphosphate [PtdIns(3,4,5)P 3 ] play key roles in chemotaxis, regulating cell motility by controlling the actin cytoskeleton in Dictyostelium and mammalian cells. PtdIns(3,4,5)P 3 , produced by PI3K, acts via diverse downstream signaling components, including the GTPase Rac, Arf-GTPases and the kinase Akt (PKB). It has become increasingly apparent, however, that chemotaxis results from an interplay between the PI3K-PTEN pathway and other parallel pathways in Dictyostelium and mammalian cells. In Dictyostelium, the phospholipase PLA2 acts in concert with PI3K to regulate chemotaxis, whereas phospholipase C (PLC) plays a supporting role in modulating PI3K activity. In adenocarcinoma cells, PLC and the actin regulator cofilin seem to provide the direction-sensing machinery, whereas PI3K might regulate motility.

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Input from Ras is required for maximal PI(3)K signalling in Drosophila

Cited by 60 publications

References 25 publications

Oncogenic signaling of class I PI3K isoforms

Oncogenic signaling of class I PI3K isoforms

Metabolically Favorable Remodeling of Human Adipose Tissue by Human Adenovirus Type 36

The regulation of cell motility and chemotaxis by phospholipid signaling

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