PTEN Regulation, a Novel Function for the p85 Subunit of Phosphoinositide 3-Kinase

Barber, Domingo F.; Alvarado-Kristensson, María; González–García, Ana; Pulido, Rafael; Carrera, Ana C.

doi:10.1126/stke.3622006pe49

Cited by 35 publications

(30 citation statements)

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“…6D). Nevertheless, in support of our data, nonphosphorylated PTEN is detected in the ϳ660-kDa gel filtration fraction (35) and dephosphorylation is a PTEN activation mechanism (16). Second, depletion of any PI3K component of the complex (p85␣, p85␤, p110␣, or p110␤) reduced PTEN activity.…”

Section: Discussionsupporting

confidence: 69%

“…Activation of p110␣ thus precedes that of p110␤ at several points in cell cycle progression (8,9,13,14), although it is not known whether p110␣ regulates p110␤ activation. The PI3K activation-induced increase in PI(3,4,5)P 3 levels is subsequently reduced to basal levels by PTEN (15)(16)(17). Various mechanisms regulate PTEN activity (16,17), although it is unclear how its activation is linked to that of PI3K.…”

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confidence: 99%

“…The PI3K activation-induced increase in PI(3,4,5)P 3 levels is subsequently reduced to basal levels by PTEN (15)(16)(17). Various mechanisms regulate PTEN activity (16,17), although it is unclear how its activation is linked to that of PI3K.…”

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confidence: 99%

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Cell Activation-Induced Phosphoinositide 3-Kinase Alpha/Beta Dimerization Regulates PTEN Activity

Pérez-García

Redondo-Muñóz

Kumar

et al. 2014

Molecular and Cellular Biology

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The phosphoinositide 3-kinase (PI3K)/PTEN (phosphatase and tensin homolog) pathway is one of the central routes that enhances cell survival, division, and migration, and it is frequently deregulated in cancer. PI3K catalyzes formation of phosphatidylinositol 3,4,5-triphosphate [PI(3,4,5)P 3 ] after cell activation; PTEN subsequently reduces these lipids to basal levels. Activation of the ubiquitous p110␣ isoform precedes that of p110␤ at several points during the cell cycle. We studied the potential connections between p110␣ and p110␤ activation, and we show that cell stimulation promotes p110␣ and p110␤ association, demonstrating oligomerization of PI3K catalytic subunits within cells. Cell stimulation also promoted PTEN incorporation into this complex, which was necessary for PTEN activation. Our results show that PI3Ks dimerize in vivo and that PI3K and PTEN activities modulate each other in a complex that controls cell PI(3,4,5)P 3 levels. The phosphoinositide 3-kinase (PI3K)/PTEN axis regulates cell survival, division, and migration. PI3Ks are lipid kinases conserved throughout evolution that catalyze phosphorylation of the third position of the inositol ring of phosphatidylinositol (PI). The PI3K family is subdivided into three classes, of which only class I generates phosphatidylinositol 3,4,5-triphosphate [PI(3,4,5)P 3 ] and, after SH2 domain-containing inositol 5=-phosphatase action, PI(3,4)P 2 (1-3). These plasma membrane components initiate signaling pathways that lead to cell activation and are downregulated by the PTEN phosphatase (1-5). Class IA PI3Ks are heterodimers composed of a 110-kDa catalytic subunit and a regulatory subunit: p85␣ (and its alternative spliced forms, p55␣ or p50␣), p85␤, or p55␥ (1-5). p85␣ and p85␤ are ubiquitous, whereas p55␥ is expressed only in certain tissues (1-5). Although four genes encode p110 subunits, only p110␣ and p110␤ are expressed ubiquitously in mammals and are more important in cancer (1-5). p110␣ and p110␤ are activated by receptor tyrosine kinases, although p110␤ can also be activated through G proteincoupled receptors (GPCRs) (6, 7). After activation, PI3K regulates processes such as cell cycling and survival (8-10).PI3K activity increases after stimulation of growth factor (GF) receptors in early G 1 phase and again in advanced G 1 . The first PI3K peak corresponds mainly to p110␣ activation, followed by a minor p110␤ activity peak; p110␣ is also activated before p110␤ in late G 1 -S-phase entry (8, 9). p110␣ is found in the cytoplasm, whereas p110␤ shuttles between the cytosol and nucleus and accumulates in the nucleus in S phase (8-10). The distinct p110␣ and p110␤ localizations and activation kinetics might reflect nonredundant roles for each isoform. p110␣ controls early G 1 events, whereas p110␤ regulates S-phase progression (8-10); p110␣ is involved in cell responses to insulin and angiogenesis (11,12), whereas p110␤ affects nuclear processes such as DNA replication and repair (9-13). p110␣ is activated again at the beginning of mitosis, followed b...

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Section: Discussionsupporting

confidence: 69%

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confidence: 99%

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Cell Activation-Induced Phosphoinositide 3-Kinase Alpha/Beta Dimerization Regulates PTEN Activity

Pérez-García

Redondo-Muñóz

Kumar

et al. 2014

Molecular and Cellular Biology

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“…16,25-27 LY and W are not ideal inhibitors to resolve this because of their off-target effects. 16 Genetic approaches have also proved problematic because of the complex makeup of the class I PI3K family 28 and the incompletely understood effects of knocking out one or more catalytic or regulatory subunits on the others. 29 Because of this, we used a chemically diverse panel of isoformspecific class I PI3K inhibitors that have been used successfully to elucidate the role of specific isoforms in various biologic processes.…”

Section: Discussionmentioning

confidence: 99%

SHIP prevents lipopolysaccharide from triggering an antiviral response in mice

Sly

Hamilton

Kuroda

et al. 2009

Blood

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Gram-negative bacterial infections, unlike viral infections, do not typically protect against subsequent viral infections. This is puzzling given that lipopolysaccharide (LPS) and double-stranded (ds) RNA both activate the TIR domain-containing adaptor-inducing interferon ␤ (TRIF) pathway and, thus, are both capable of eliciting an antiviral response by stimulating type I interferon (IFN) production. We demonstrate herein that SH2-containing inositol-5-phosphatase (SHIP) protein levels are dramatically increased in murine macrophages via the MyD88-dependent pathway, by up-regulating autocrine-acting transforming growth factor-␤ (TGF␤). The increased SHIP then mediates, via inhibition of the phosphatidylinositol-3-kinase (PI3K) pathway, cytosine-phosphate-guanosine (CPG)-and LPS-induced tolerance and cross-tolerance and restrains IFN-␤ production induced by a subsequent exposure to LPS or dsRNA. Intriguingly, we found, using isoform-specific PI3K inhibitors, that LPSor cytosine-phosphate-guanosine-induced interleukin-6 (IL-6) is positively regulated by p110␣, -␥, and -␦ but negatively regulated by p110␤. This may explain some of the controversy concerning the role of PI3K in Tolllike receptor-induced cytokine production. Consistent with our in vitro findings, SHIP ؊/؊ mice overproduce IFN-␤ in response to LPS, and this leads to antiviral hypothermia. Thus, up-regulation of SHIP in response to Gram-negative bacterial infections probably explains the inability of such infections to protect against subsequent viral infections. (Blood. 2009;113: 2945-2954) IntroductionWe reported in 2004 that the hematopoietic-restricted, SH2-containing inositol-5Ј-phosphatase (SHIP, also known as SHIP1) was markedly up-regulated in bone marrow-derived macrophages (BMms) and mast cells (BMMCs) on exposure to lipopolysaccharide (LPS, also known as endotoxin). 1 This increase in SHIP was mediated by the production of autocrine-acting transforming growth factor-␤ (TGF-␤) and blocked the production of proinflammatory cytokines and nitric oxide in response to a subsequent exposure to LPS. 1 Consistent with these results, we found that SHIP Ϫ/Ϫ BMms, BMMCs, and SHIP Ϫ/Ϫ mice did not display endotoxin tolerance. 1 Several questions arose as a result of this study, including whether SHIP plays a role in the tolerance induced by Toll-like receptors (TLRs) other than TLR4, whether TGF-␤ and SHIP are up-regulated via the MyD88-dependent or -independent pathway, and whether SHIP negatively regulates both of these pathways. To address these questions, we took advantage of differences in signaling initiated by TLR3, TLR4, and TLR9.TLR3, in response to binding double-stranded RNA (dsRNA) in endosomes, activates cells exclusively through MyD88-independent pathways by recruiting TRIF, which activates the IB kinase (IKK)-related kinases, TBK1 and IKK-⑀. These, together with the adaptors TANK and NAP1, phosphorylate the transcription factor IRF3, allowing it to dimerize and translocate to the nucleus where it collaborates with nuclear factor-B (NF-B) a...

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“…In recent years, several groups have reported mutations or gene amplifications in the PI3K p110α catalytic subunit resulting in increased pathway signaling (1)(2)(3). The tumor suppressor protein phosphatase and tensin homologue (PTEN) acts to inhibit PI3K pathway signaling and is commonly mutated, deleted, or epigenetically repressed in human cancers (4,5). In addition, the pathway can be activated by mutations or overexpression of upstream signaling molecules such as epidermal growth factor receptor (EGFR) or ErbB2 (6)(7)(8).…”

Section: Introductionmentioning

confidence: 99%

Isoform-Specific Phosphoinositide 3-Kinase Inhibitors Exert Distinct Effects in Solid Tumors

Edgar¹,

Wallin²,

Berry³

et al. 2010

Cancer Research

111

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Therapeutic inhibitors are being developed against the phosphoinositide 3-kinase (PI3K) pathway, the deregulation of which drives tumor growth and survival in many cancers. There are eight PI3Ks in mammals divided into three classes. Class IA PI3Ks (p110α, p110β, and p110δ) are critical for cell growth and survival, with the p110α isoform implicated as the most important in carcinomas. In this study, we examined the effects of small-molecule inhibitors of class IA PI3Ks to explore the contributions of different isoforms in cancer cells. Similar responses were seen in cancer cells with wild-type or activated mutant PI3K genes treated with p110α/δ or p110α/β/δ inhibitors in cell viability assays. In contrast, PTEN-negative cell lines tended to be less responsive (4-fold overall) to an inhibitor of p110α/δ versus p110α/β/δ. Combining a p110α/δ inhibitor with a p110β inhibitor resulted in comparable potency to the p110α/β/δ inhibitor. The disparity in efficacy was confirmed in vivo. Pharmacodynamic biomarker analysis revealed that an inhibitor with insufficient potency against the p110β isoform was less effective at inhibiting the PI3K pathway in PTEN-negative tumor xenografts. Our results imply that patients with PTEN-negative tumors may preferentially benefit from treatment with a class I PI3K inhibitor that is capable of inhibiting the p110β isoform.

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PTEN Regulation, a Novel Function for the p85 Subunit of Phosphoinositide 3-Kinase

Cited by 35 publications

References 34 publications

Cell Activation-Induced Phosphoinositide 3-Kinase Alpha/Beta Dimerization Regulates PTEN Activity

Cell Activation-Induced Phosphoinositide 3-Kinase Alpha/Beta Dimerization Regulates PTEN Activity

SHIP prevents lipopolysaccharide from triggering an antiviral response in mice

Isoform-Specific Phosphoinositide 3-Kinase Inhibitors Exert Distinct Effects in Solid Tumors

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