The activation of phosphatidylinositol 3-kinase by Ras

Kodaki, Tsutomu; Woscholski, Rüdiger; Hållberg, Bengt; Downward, Julian; Parker, Peter J.

doi:10.1016/s0960-9822(00)00177-9

Cited by 299 publications

(208 citation statements)

References 45 publications

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“…While several lines of evidence suggest that PI 3-kinase is a downstream e ector of Ras (Khwaja et al, 1997;Klinghofer et al, 1996;Kodaki et al, 1994;Rodriguez-Viciana et al, 1994, 1996, there have also been less direct indications that PI 3-kinase might be able to act as an upstream regulator of Ras under some circumstances (Hu et al, 1995). In order to investigate whether the levels of PI 3-kinase activity induced by NGF stimulation of PC12 cells might be able to directly in¯uence the activation state of Ras, a mutant form of Trk which lacked the ability to autophosphorylate at Y490 or Y785 and also lacked a juxtamembrane motif implicated in induction of neuronal di erentiation (KGF, (Peng et al, 1995)) but contained an arti®cial p85 binding site, was expressed in nnr5 cells (Y490F/Y785F/ DKGF+YxxM at L605).…”

Section: Discussionmentioning

confidence: 99%

“…In addition, we have measured the levels of PI 3-kinase product lipids in intact PC12 cells in response to NGF treatment, and show that PI 3-kinase activation normally correlates with Ras. To distinguish between models in which Ras acts upstream of PI 3-kinase (Klinghofer et al, 1996;Kodaki et al, 1994;Rodriguez-Viciana et al, 1994, 1996, or PI 3-kinase acts upstream of Ras (Hu et al, 1995), a mutant Trk lacking the major autophosphorylation sites, but with an added YxxM p85 binding motif, was analysed. This mutant fails to activate Ras, despite fully activating PI 3-kinase, indicating that physiological activation of PI 3-kinase alone is insu cient to activate Ras, and arguing against a PI 3-kinase upstream of Ras model.…”

Section: Introductionmentioning

confidence: 99%

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Nerve growth factor induced stimulation of Ras requires Trk interaction with Shc but does not involve phosphoinositide 3-OH kinase

et al. 1998

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The TrkA receptor protein tyrosine kinase is involved in signalling PC12 cell di erentiation and cessation of cell division in response to nerve growth factor (NGF). To assess the importance of adaptor proteins and Ras in NGF control of phosphoinositide 3-OH kinase (PI 3-kinase), speci®c receptor mutations in Trk have been employed. We show that phosphorylation of tyrosine 490, but not 785, of Trk is essential for activation of both Ras and PI 3-kinase in vivo, correlating with tyrosine phosphorylation of Shc and binding of Shc to the adaptor Grb2 and the Ras exchange factor Sos. A mutant receptor that lacks Y490 and Y785, but contains an introduced YxxM motif which binds the regulatory domain of PI 3-kinase, is unable to activate Ras despite causing increased PI 3-kinase activity. This indicates clearly that activation of PI 3-kinase by itself is not su cient to cause activation of Ras, arguing against a model in which PI 3-kinase acts upstream of Ras. The Shc site of Trk is thus crucial for the activation of Ras and PI 3-kinase.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Nerve growth factor induced stimulation of Ras requires Trk interaction with Shc but does not involve phosphoinositide 3-OH kinase

et al. 1998

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“…Active Ras binds to the p110 subunit of PI3-kinase and stimulates its activity in vivo (Rodriguez-Viciana et al 1994;Kodaki et al, 1994). However, expression of a constitutively activated form of PI3-kinase activates Ras and induces Ras-dependent maturation in Xenopus oocytes (Hu et al, 1995).…”

Section: Discussionmentioning

confidence: 99%

Inhibition of the MAP kinase cascade blocks heregulin-induced cell cycle progression in T-47D human breast cancer cells

et al. 1998

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Members of the erbB family of receptor tyrosine kinases are commonly overexpressed in human breast cancer. However, the relative contribution of particular signalling pathways activated downstream of these receptors to the mitogenic response of transformed breast epithelial cells remains poorly characterized. Administration of heregulin-b2 (HRG), a ligand for erbB3 and erbB4, to growth arrested T-47D human breast cancer cells leads to activation of both the PI3-kinase and MAP kinase signalling pathways and potent stimulation of cell cycle progression. Speci®c inhibitors were used to assess the role of these pathways in HRG-induced mitogenesis and to identify underlying mechanisms in terms of regulation of gene expression. Treatment with the MEK inhibitor PD98059 led to a complete block of HRG-induced entry into S-phase, whilst administration of the PI3-kinase inhibitor wortmannin resulted in only modest inhibition. In addition, administration of PD98059 8 h after HRG was equipotent with simultaneous administration in inhibiting entry into S-phase. However, delaying addition for 14 ± 16 h after HRG, when the cells were entering Sphase, was without e ect. HRG stimulation led to sequential induction of c-myc, cyclin D1, cyclin E and cyclin A gene expression and hyperphosphorylation of the retinoblastoma protein pRB. p21 (WAF1/CIP1/ SDI1) gene expression was rapidly induced by HRG, but signi®cant changes in p27 (KIP1) protein levels were not detected. Preincubation with PD98059 blocked the HRG-dependent induction of cyclin D1 mRNA, p21 and c-Myc protein and pRB phosphorylation. These ®ndings demonstrate that MEK activation is critical to HRGinduced S-phase entry in these cells whilst PI3-kinase plays a minor role. Moreover, these data are compatible with HRG-induced activation of MEK being critical for a mid-G1 transition point and implicate c-myc and cyclin D1 as key targets of the MAP kinase pathway involved in this response.

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“…In intact cells, there is evidence that Ras can stimulate PI3K activity and is required for its optimal activation in response to growth factors (Kodaki et al, 1994;RodriguezViciana et al, 1994). Furthermore, dominant negative Ras inhibited platelet-derived growth factor (PDGF) activation of PI3K.…”

Section: Ras Mediates Its Actions Through Interaction With Multiple Ementioning

confidence: 99%

“…Although the e ect of Ras on PI3K activity in vitro is modest (*twofold) using bacterially expressed recombinant Ras, it is possible that like Raf-1, PI3K activation requires posttranslational modi®cation of Ras and/or other factors to achieve full stimulation of PI3K activity (Kodaki et al, 1994). In fact, is has been recently shown that Ras-GTP can activate the lipid kinase activity of PI3K directly in vitro and that this e ect is synergistic with tyrosine phosphopeptide binding to p85 (Rodriguez-Viciana et al, 1996).…”

Section: Ras Mediates Its Actions Through Interaction With Multiple Ementioning

confidence: 99%

Increasing complexity of Ras signaling

et al. 1998

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The initial discovery that ras genes endowed retroviruses with potent carcinogenic properties and the subsequent determination that mutated ras genes were present in a wide variety of human cancers, prompted a strong suspicion that the growth-promoting actions of mutated Ras proteins contribute to their aberrant regulation of growth stimulatory signaling pathways. In 1993, a remarkable convergence of experimental observations from genetic analyses of Drosophila, S. cerevisiae and C. elegans as well as biochemical and biological studies in mammalian cells came together to de®ne a clear role for Ras in signal transduction. What emerged was an elegant linear signaling pathway where Ras functions as a relay switch that is positioned downstream of cell surface receptor tyrosine kinases and upstream of a cytoplasmic cascade of kinases that included the mitogen-activated protein kinases (MAPKs). Activated MAPKs in turn regulated the activities of nuclear transcription factors. Thus, a signaling cascade where every component between the cell surface and the nucleus was de®ned and conserved in worms,¯ies and man. This was a remarkable achievement in our e orts to appreciate how the aberrant function of Ras proteins may contribute to the malignant growth properties of the cancer cell. However, the identi®cation of this pathway has proven to be just the beginning, rather than the culmination, of our understanding of Ras in signal transduction. Instead, we now appreciate that this simple linear pathway represents but a minor component of a very complex signaling circuitry. Ras signaling has emerged to involve a complex array of signaling pathways, where cross-talk, feedback loops, branch points and multi-component signaling complexes are recurring themes. The simplest concept of a signaling cascade, where each component simply relays the same message to the next, is clearly not the case. In this review, we summarize our current understanding of Ras signal transduction with an emphasis on new complexities associated with the recognition and/or activation of cellular e ectors, and the diverse array of signaling pathways mediated by interaction between Ras and Ras-subfamily proteins with multiple e ectors.

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The activation of phosphatidylinositol 3-kinase by Ras

Cited by 299 publications

References 45 publications

Nerve growth factor induced stimulation of Ras requires Trk interaction with Shc but does not involve phosphoinositide 3-OH kinase

Nerve growth factor induced stimulation of Ras requires Trk interaction with Shc but does not involve phosphoinositide 3-OH kinase

Inhibition of the MAP kinase cascade blocks heregulin-induced cell cycle progression in T-47D human breast cancer cells

Increasing complexity of Ras signaling

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