Essential Role of Phosphoinositide 3-Kinase δ in Neutrophil Directional Movement

Sadhu, Chanchal; Masinovsky, Boris; Dick, Ken O.; Sowell, C. Gregory; Staunton, Donald E.

doi:10.4049/jimmunol.170.5.2647

Cited by 351 publications

(337 citation statements)

References 49 publications

Supporting

Mentioning

315

Contrasting

Unclassified

Order By: Relevance

“…Studies with these inhibitors support the following conclusions: (1) p110a is the primary insulin responsive PI3K in adipocytes and myotubes and is the major PI3K associated with insulin receptor substrate-1 (IRS-1) , (2) p110b contributes to the pathogenesis of arterial thrombosis (Jackson et al, 2005), (3) p110g mediates inflammation in a model of rheumatoid arthritis (Camps et al, 2005) and (4) p110d is an essential component of neutrophil directional movement (Sadhu et al, 2003) and plays a role in cell proliferation of acute myeloid leukemia (Sujobert et al, 2005).…”

Section: Introductionmentioning

confidence: 88%

See 1 more Smart Citation

Oncogenic signaling of class I PI3K isoforms

et al. 2007

View full text Add to dashboard Cite

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.

show abstract

Section: Introductionmentioning

confidence: 88%

“…Recently isoform-specific small-molecule inhibitors have been described for p110b (Jackson et al, 2005), p110d (Sadhu et al, 2003) and p110g (Camps et al, 2005). These compete with ATP and inhibit the kinase activity of the catalytic subunit.…”

Section: Inhibition Of Class I Pi3k Isoforms By Isoform-specific Inhimentioning

confidence: 99%

Oncogenic signaling of class I PI3K isoforms

et al. 2007

View full text Add to dashboard Cite

show abstract

“…The rIL-2 standard was from BioLegend. The p110␦-selective inhibitor IC (37,38) was dissolved in DMSO. WM and LY294002 were purchased from Calbiochem and dissolved in DMSO.…”

Section: Abs and Reagentsmentioning

confidence: 99%

“…Similar results were observed using LY294002 inhibitor (data not shown). Because the PI3K catalytic subunit p110␦ contributes a significant proportion of PI3K signaling in B cells (31)(32)(33), we examined the role of this isoform, using the p110␦-selective inhibitor IC (37,38) and B cells from mice carrying an inactivating mutation of p110␦ (33). Pretreatment of normal B cells with IC partially inhibited their ability to induce IL-2 production in a dose-dependent fashion (Fig.…”

Section: The P110␦ Signaling Is Required For Bcr-mediated Ag Presentamentioning

confidence: 99%

Requirement for Phosphoinositide 3-Kinase p110δ Signaling in B Cell Antigen Receptor-Mediated Antigen Presentation

Al‐Alwan

Okkenhaug

Vanhaesebroeck

et al. 2007

The Journal of Immunology

View full text Add to dashboard Cite

The BCR serves to both signal cellular activation and enhance uptake and presentation of Ags by B cells; however, the intracellular signaling mechanisms linking the BCR to Ag presentation functions have been controversial. PI3Ks are critical signaling enzymes controlling many cellular processes, with the p110δ isoform playing a critical role in BCR signaling. In this study, we used pharmacological and genetic approaches to evaluate the role of p110δ signaling in Ag presentation by primary B lymphocytes. It was found that activation of allogeneic T cells is significantly reduced when B cells are pretreated with global PI3K inhibitors, but was intact when p110δ signaling was specifically inactivated. In contrast, inactivation of p110δ significantly impaired the ability of B cells to activate T cells in a BCR-mediated Ag uptake and presentation model. Prestimulation of p110δ-inactivated B cells with anti-CD40 or LPS could not rescue their BCR-mediated Ag presentation ability to normal levels. p110δ signaling was required for efficient presentation of either anti-Ig or protein Ag via a lysozyme-specific BCR. p110δ-inactivated B cells were able to internalize Ag normally, and no defects in association of Ag with lysosome-associated membrane protein 1+ late endosomes were observed; however, these cells were less effective in forming polarized conjugates with Ag-specific T cells. Our data demonstrate a role for p110δ signaling in B cell Ag presentation function, implicating 3-phosphoinositides and their targets in the latter stages of this process.

show abstract

“…Arguing against the possibility of redundancy and compensating activity from other PI3K isoforms, treating the amoebae with the PI3K inhibitors also results in similarly mild defects (5). More pronounced effects have been reported for neutrophils lacking the G protein-regulated PI3K␥ gene, but even in this system there does not appear to be an absolute requirement for PIP 3 because studies using PI3K inhibitors have only partial effects (14,40,50 3 at the front and PTEN focuses the distribution of this lipid by degrading it as it diffuses outside of this region (FIGURE 2).…”

Section: Figure 1 Chemotactic Migrationmentioning

confidence: 99%