Signaling by Distinct Classes of Phosphoinositide 3-Kinases

Vanhaesebroeck, Bart; Waterfield, Michael D.

doi:10.1006/excr.1999.4701

Cited by 800 publications

(726 citation statements)

References 174 publications

(180 reference statements)

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“…Recent studies suggest that PI3K plays a pivotal role in the recruitment and activation of eosinophils by induction of the Th2 response (Palframan et al, 1998;Myou et al, 2003;Lee et al, 2006a). PI3K is a signal transduction enzyme, which phosphorylates the D3 position of the inositol ring of phosphoinositide and its phosphorylated derivatives (Vanhaesebroeck and Waterfield, 1999). This phosphorylation then stimulates the catalytic activity of Akt, resulting in the subsequent phosphorylation of a host of other proteins which affect cell growth, cell cycle entry, and cell survival (Datta et al, 1997).…”

Section: Discussionmentioning

confidence: 99%

Potential use of an anticancer drug gefinitib, an EGFR inhibitor, on allergic airway inflammation

Hur

Lee²,

Lee³

et al. 2007

Exp Mol Med

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The EGFR plays an essential role in goblet cell hyperplasia and mucus hypersecretion. EGFR has an intrinsic tyrosine kinase activity that, when activated, induces the production of MUC5AC through the signaling kinase cascade in the airway epithelium. We have investigated the effects of an EGFR tyrosine kinase inhibitor, gefitinib, on ovalbumin (OVA)-induced, allergic inflammation in airway epithelia of mice. OVA-sensitized mice were pretreated with gefitinib at two different doses (12.5 and 50 mg/kg) and then challenged with OVA. The OVA challenge increased the total cell count and eosinophil count in bronchoalveolar lavage fluid (BALF), as well as the concentrations of T-helper2 (Th2) cytokines, such as IL-4 and IL-13, overall eosinophil recruitment in the lung tissue and airway hyperresponsiveness (AHR). Pretreatment with gefitinib reduced the inflammatory cell counts and released cytokine concentrations (IL-4 and IL-13) in BALF, as well as eosinophil recruitment in the lungs and AHR, in a dose-dependent manner. This was associated with decreased EGFR and Akt phosphorylation. We showed that gefitnib inhibits EGFR and phosphoinositol 3'-kinase (PI3K)/Akt activation which were activated in OVA sensitized mice. These findings suggest that inhibitors of the EGFR cascade may have a role in the treatment of asthma.

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Section: Discussionmentioning

confidence: 99%

Potential use of an anticancer drug gefinitib, an EGFR inhibitor, on allergic airway inflammation

Hur

Lee²,

Lee³

et al. 2007

Exp Mol Med

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“…PI3Ks are a family of kinases that phosphorylate the 3 -OH position of the inositol ring of phosphoinositides [93]. There are three classes of PI3Ks: class I PI3Ks are dimers consisting of a catalytic and a regulatory subunit, class II PI3Ks are large molecules which contain a C terminal C2 domain, and class III PI3Ks are homologues of the yeast protein Vps34p.…”

Section: Phosphoinositide 3-kinase (Pi3k) and Other Signaling Eventsmentioning

confidence: 99%

Chemokines: attractive mediators of the immune response

Wong

Fish

2003

Seminars in Immunology

229

186

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“…Different combinations of regulatory and catalytic subunits distinguish the three major classes of PI3Ks and confer diverse substrate specificity and mechanism of upstream signaling (1)(2)(3). Class I PI3Ks include four isoforms consisting of two subdivisions, class IA (PI3Kα, β, δ) and class IB (PI3Kγ).…”

Section: Introductionmentioning

confidence: 99%

Structure-Based Design of an Organoruthenium Phosphatidyl-inositol-3-kinase Inhibitor Reveals a Switch Governing Lipid Kinase Potency and Selectivity

et al. 2008

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Mutations that constitutively activate the PI3K signaling pathway, including alterations in PI3K, PTEN and AKT are found in a variety of human cancers, implicating the PI3K lipid kinase as an attractive target for the development of therapeutic agents to treat cancer and other related diseases. In this study, we report on the combination of a novel organometallic kinase inhibitor scaffold with structure-based design to develop a PI3K inhibitor, called E5E2, with an IC 50 potency in the mid-low-nanomolar range and selectivity against a panel of protein kinases. We also show that E5E2 inhibits phospho-AKT in human melanoma cells and leads to growth inhibition. Consistent with a role for the PI3K pathway in tumor cell invasion, E5E2 treatment also inhibits the migration of melanoma cells in a 3D spheroid assay. The structure of the PI3Kγ/ E5E2 complex reveals the molecular features that give rise to this potency and selectivity towards lipid kinases with implications for the design of a subsequent generation of PI3K-isoform specific organometallic inhibitors.

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Signaling by Distinct Classes of Phosphoinositide 3-Kinases

Cited by 800 publications

References 174 publications

Potential use of an anticancer drug gefinitib, an EGFR inhibitor, on allergic airway inflammation

Potential use of an anticancer drug gefinitib, an EGFR inhibitor, on allergic airway inflammation

Chemokines: attractive mediators of the immune response

Structure-Based Design of an Organoruthenium Phosphatidyl-inositol-3-kinase Inhibitor Reveals a Switch Governing Lipid Kinase Potency and Selectivity

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