PI3Kγ inhibition blocks glomerulonephritis and extends lifespan in a mouse model of systemic lupus

Barber, Domingo F.; Bartolomé, A.; Hernández, Carmen; Flores, Juana M.; Redondo, Clara; Fernández-Arias, Cristina; Camps, Montserrat; Rückle, Thomas; Schwarz, Matthias; Rodríguez, S. Sánchez; Martı́nez-A, Carlos; Balomenos, Dimitrios; Rommel, Christian; Carrera, Ana C.

doi:10.1038/nm1291

Cited by 305 publications

(258 citation statements)

References 11 publications

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“…Newly identified inhibitors which all compete with ATP for binding to the kinase active site have been useful tools in elucidating the role of p110 isoforms in various pathologies such as growth and metabolic regulation , asthma (Ali et al, 2004), inflammation (Barber et al, 2005), arthritis (Camps et al, 2005) and thrombosis (Jackson et al, 2005). Our data show that isoform-specific inhibitors can block the oncogenicity of class I PI3Ks.…”

Section: Oncogenic Signaling Of Class I Pi3k Isoforms a Denley Et Almentioning

confidence: 77%

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: Oncogenic Signaling Of Class I Pi3k Isoforms a Denley Et Almentioning

confidence: 77%

Oncogenic signaling of class I PI3K isoforms

et al. 2007

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“…In addition, our results suggest that blocking the PI(3)Kg by AS 605402 can effectively interfere with loss of endothelial barrier function provoked by vGPCR, therefore placing PI(3)Kg activity as a multi-functional molecular target for the treatment of patients with KS. Of note, suppression of PI (3)Kg action has been successfully tested in animal models for several pro-angiogenic and pro-inflammatory diseases, such as retinal hyper-permeability, glomerulonephritis, joint inflammation and rheumatoid arthritis (Barber et al, 2005;Camps et al, 2005;Gavard et al, 2009).…”

Section: Discussionmentioning

confidence: 99%

Remodeling of VE-cadherin junctions by the human herpes virus 8 G-protein coupled receptor

et al. 2010

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Kaposi Sarcoma (KS) are opportunistic tumors, associated with human herpes virus 8 (HHV8) infection. KS development is highly favored by immune-depression and remains the second most frequent tumor in acquired immune deficiency syndrome patients. Although it has been shown that experimental expression of the HHV8 G-proteincoupled receptor (vGPCR) in the endothelial compartment is alone sufficient to recapitulate the formation and progression of KS-like lesions, its functional effects on endothelial homeostasis are not fully understood. Here we show that vGPCR expression in endothelial cells induces an increase in paracellular permeability both in vivo and in vitro. By using pharmacological inhibitors and small interference RNA-based knockdown, we demonstrate an essential role for the PI(3)Kinase-c/Rac nexus in vGPCRmediated permeability. This was further accompanied by dramatic remodeling of VE-cadherin-dependent cell-cell junctions. Importantly, this in vitro vGPCR-initiated signaling signature was observed in a large panel of human KS. Altogether, our results support the hypothesis that endothelial vGPCR signaling is co-opted in KS, and unveil new key cellular targets for therapeutic intervention.

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“…However, some reports suggested that class IA PI3K might also be activated by GPCRs and may play a role in chemokine receptor-mediated IL-1␤ induction in primary human monocytes (35)(36)(37)(38). To define the role of specific PI3K isoforms on gp120-stimulated IL-1␤ release, we used the class IA PI3K-specific inhibitor PI-103 (39) and the class IB PI3K specific inhibitor AS605240 (40,41). As shown in Fig.…”

Section: Activation Of Pi3k Is Necessary For Gp120-triggered Il-1␤ Inmentioning

confidence: 99%

Signaling Mechanism of HIV-1 gp120 and Virion-Induced IL-1β Release in Primary Human Macrophages

Cheung

Ravyn

Wang

et al. 2008

The Journal of Immunology

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HIV-1 envelope glycoprotein gp120 induces, independently of infection, the release of proinflammatory cytokines, including IL-1β from macrophages, that are implicated in the pathogenesis of HIV-associated dementia. However, the signal transduction pathways involved have not been fully defined. Previously, our laboratory reported that soluble gp120 activates multiple protein kinases in primary human monocyte-derived macrophages, including the Src family kinase Lyn, PI3K, and the focal adhesion-related proline-rich tyrosine kinase Pyk2. In this study we showed that gp120 induces IL-1β release from macrophages in a time- and concentration-dependent manner through binding to the chemokine receptor CCR5 and coupling to Giα protein. Using pharmacological inhibitors and small interfering RNA gene knockdown, we demonstrated that concomitant activation of Lyn, Pyk2, and class IA PI3K are required for gp120-induced IL-1β production. By coimmunoprecipitation and immunofluorescence confocal microscopy, we showed that CCR5 activation by gp120 triggered the assembly of a signaling complex involving endogenous Lyn, PI3K, and Pyk2 and is associated with PI3K and Pyk2 translocation from the cytoplasm to the membrane where they colocalized with Lyn. Finally, we demonstrated that virion-associated gp120 induced similar response, as structurally intact whole virions also triggered IL-1β release and re-localization of PI3K and Pyk2. This study identifies a novel signaling mechanism for HIV-1-induced IL-1β production by primary human macrophages that may be involved in the neuropathogenesis of HIV-associated dementia.

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PI3Kγ inhibition blocks glomerulonephritis and extends lifespan in a mouse model of systemic lupus

Cited by 305 publications

References 11 publications

Oncogenic signaling of class I PI3K isoforms

Oncogenic signaling of class I PI3K isoforms

Remodeling of VE-cadherin junctions by the human herpes virus 8 G-protein coupled receptor

Signaling Mechanism of HIV-1 gp120 and Virion-Induced IL-1β Release in Primary Human Macrophages

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