Angiogenesis selectively requires the p110α isoform of PI3K to control endothelial cell migration

Graupera, Mariona; Guillermet-Guibert, Julie; Foukas, Lazaros C.; Phng, Li-Kun; Cain, Robert J.; Salpekar, Ashreena; Pearce, Wayne; Meek, Stephen; Millán, Jaime; Cutillas, Pedro R.; Smith, Andrew J.H.; Ridley, Anne J.; Ruhrberg, Christiana; Gerhardt, Holger; Vanhaesebroeck, Bart

doi:10.1038/nature06892

Cited by 461 publications

(474 citation statements)

References 26 publications

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“…3c), which differed from the effects of p110α knockdown [10][11][12][13] . However, C2α knockdown markedly inhibited VEGF-A-induced phosphorylation of MYPT1, a substrate of Rho kinase (Fig.…”

Section: C2α Is Involved In Endothelial Migration Proliferation and mentioning

confidence: 94%

“…These C2α actions underlie its roles in angiogenesis and barrier integrity. The actions of C2α and class I PI3Ks in EC are distinct in that, different from C2α, class I PI3Ks exert a great impact on Akt stimulation and cell proliferation and are not involved in vesicular trafficking including VE-cadherin transfer or VE-cadherin assembly at the cell-cell junction [10][11][12][13] . Therefore, these observations reveal novel biological activities of C2α and underscore broader roles for PI3K family members in vascular physiology and pathophysiology.…”

Section: Discussionmentioning

confidence: 99%

“…Class I PI3Ks, which are activated by tyrosine kinases and G protein-coupled receptors, consist of four catalytic subunits: p110α, p110β, p110γ and p110δ, and mainly produce phosphatidylinositol (PtdIns) 3,4,5-trisphosphates (PtdIns(3,4,5)P 3 ). Class I PI3Ks, especially p110α, in EC are indispensable for angiogenesis in the early embryo by regulating EC proliferation, migration and morphogenesis 13,14 . Class III has a single member, Vps34, which generates PtdIns(3)P to regulate vesicular trafficking 15 .…”

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confidence: 99%

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Endothelial PI3K-C2α, a class II PI3K, has an essential role in angiogenesis and vascular barrier function

Yoshioka

Yoshida

Chen

et al. 2012

Nat Med

186

263

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Class II α-isoform of phosphatidylinositol 3-kinases (PI3K-C2α) is localized in endosomes, the trans-Golgi network and clathrin-coated vesicles, however, its functional role is little understood. Global or endothelial cell (EC)-specific targeted disruption of PI3K-C2α resulted in embryonic lethality due to defects in sprouting angiogenesis and vascular maturation. PI3K-C2α knockdown in ECs induced decreased phospatidylinositol 3-phosphate-enriched endosomes, impaired endosomal trafficking, and defective delivery of VE-cadherin to EC junctions and its assembly. PI3K-C2α knockdown also impeded cell signaling including vascular endothelial growth factor receptor internalization and endosomal RhoA activation. These together led to defective EC migration, proliferation, tube formation and barrier integrity. Endothelial PI3K-C2α deletion suppressed post-ischemic and tumor angiogenesis, and diminished vascular barrier function, with greatly augmented susceptibility to anaphylaxis and a higher incidence of dissecting aortic aneurysm formation in response to angiotensin II infusion. Thus, PI3K-C2α plays a crucial role in vascular formation and barrier integrity, and represents a new therapeutic target for vascular diseases. 3Formation of the vascular network by vasculogenesis and angiogenesis is essential for embryonic development, repair and remodeling of tissues in adults, as well as tumor growth. The angiogenic response to vascular endothelial growth factor (VEGF) and other factors begins with vascular leakage and dissolution of the subendothelial basement membrane, followed by proliferation and migration of vascular EC 1,2 . Then, formation of the intercellular junctions results in initial sprouts from existing vessels. The newly formed endothelial tubes are associated with mural cells, i.e. smooth muscle cells (SMC) and pericytes, thus becoming mature and stabilized 3 . Tightness of the intercellular junctions, particularly adherens junctions composed of VE-cadherin, controls vascular permeability 4,5 . Quiescent, stabilized vasculature with intact barrier integrity dominates in the healthy condition. In contrast, in pathological conditions, such as tumors, the vasculature is generally inmaturate and leaky. In the case of vascular insult such as excessive angiotensin II (Ang II) activity, increased vascular permeability is asssociated with leukocyte infiltration in the vascular wall and vascular disruption 6,7 . Therefore, stabilization of the vasculature and maintenance of vascular integrity is essential for vascular and tissue homeostasis 8,9 .PI3Ks are an enzyme family that phosphorylates membrane inositol lipids at the 3' position of the inositol ring. The lipid products of PI3Ks serve as important intracellular messengers by interacting with effector proteins, which include protein kinases, guanine nucleotide exchangers for G proteins, and actin cytoskeleton-regulating proteins. Through these actions, PI3Ks regulate a diverse array of cellular processes 10-12 .PI3Ks comprise three classes. Class I PI...

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Section: C2α Is Involved In Endothelial Migration Proliferation and mentioning

confidence: 94%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

See 1 more Smart Citation

Endothelial PI3K-C2α, a class II PI3K, has an essential role in angiogenesis and vascular barrier function

Yoshioka

Yoshida

Chen

et al. 2012

Nat Med

186

263

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“…However, recent studies have demonstrated that the p110a and p110b isoforms play distinct roles in cellular signaling, growth, and oncogenic transformation. It has been shown in mice, for example, that both p110a and p110b contribute to insulin action in the liver (Foukas et al 2006;Ciraolo et al 2008;Jia et al 2008;Sopasakis et al 2010), whereas angiogenesis and vascular endothelial growth factor (VEGF) signaling require p110a but not p110b (Graupera et al 2008). Interestingly, while p110a is essential for lung adenocarcinoma induced by Kras (Gupta et al 2007), p110b is required for prostate tumorigenesis driven by Pten loss in mice (Jia et al 2008).…”

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confidence: 99%

The p110α and p110β isoforms of PI3K play divergent roles in mammary gland development and tumorigenesis

Utermark¹,

Rao²,

Cheng³

et al. 2012

Genes Dev.

123

115

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Class Ia phosphatidylinositol 3 kinase (PI3K) is required for oncogenic receptor-mediated transformation; however, the individual roles of the two commonly expressed class Ia PI3K isoforms in oncogenic receptor signaling have not been elucidated in vivo. Here, we show that genetic ablation of p110a blocks tumor formation in both polyoma middle T antigen (MT) and HER2/Neu transgenic models of breast cancer. Surprisingly, p110b ablation results in both increased ductal branching and tumorigenesis. Biochemical analyses suggest a competition model in which the less active p110b competes with the more active p110a for receptor binding sites, thereby modulating the level of PI3K activity associated with activated receptors. Our findings demonstrate a novel p110b-based regulatory role in receptor-mediated PI3K activity and identify p110a as an important target for treatment of HER2-positive disease.

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“…On the other hand, there are several cancer types that have been reported to have elevated levels and/or genomic amplifications of these other isoforms, indicating that they too may contribute to cancer (13,14). In addition, activation of receptor tyrosine kinases such as VEGF receptor, EGF receptor, PDGF receptor, or human epidermal growth factor receptor 2 (HER2) leading to the activation of the PI3K pathway usually requires p110α for signaling and tumorigenesis (15)(16)(17). Rat sarcoma (Ras) proteins, which signal in part through PI3K pathway, are also frequently mutated in human cancer (18,19).…”

mentioning

confidence: 99%

PI3K isoform dependence of PTEN-deficient tumors can be altered by the genetic context

Schmit

Utermark

Zhang

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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There has been increasing interest in the use of isoform-selective inhibitors of phosphatidylinositide-3-kinase (PI3K) in cancer therapy. Using conditional deletion of the p110 catalytic isoforms of PI3K to predict sensitivity of cancer types to such inhibitors, we and others have demonstrated that tumors deficient of the phosphatase and tensin homolog (PTEN) are often dependent on the p110β isoform of PI3K. Because human cancers usually arise due to multiple genetic events, determining whether other genetic alterations might alter the p110 isoform requirements of PTEN-null tumors becomes a critical question. To investigate further the roles of p110 isoforms in PTEN-deficient tumors, we used a mouse model of ovarian endometrioid adenocarcinoma driven by concomitant activation of the rat sarcoma protein Kras, which is known to activate p110α, and loss of PTEN. In this model, ablation of p110β had no effect on tumor growth, whereas p110α ablation blocked tumor formation. Because ablation of PTEN alone is often p110β dependent, we wondered if the same held true in the ovary. Because PTEN loss alone in the ovary did not result in tumor formation, we tested PI3K isoform dependence in ovarian surface epithelium (OSE) cells deficient in both PTEN and p53. These cells were indeed p110β dependent, whereas OSEs expressing activated Kras with or without PTEN loss were p110α dependent. Furthermore, isoform-selective inhibitors showed a similar pattern of the isoform dependence in established Kras G12D /PTEN-deficient tumors. Taken together, our data suggest that, whereas in some tissues PTEN-null tumors appear to inherently depend on p110β, the p110 isoform reliance of PTEN-deficient tumors may be altered by concurrent mutations that activate p110α.ovarian cancer | PI3K inhibitors | genetically engineered mouse model

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Angiogenesis selectively requires the p110α isoform of PI3K to control endothelial cell migration

Cited by 461 publications

References 26 publications

Endothelial PI3K-C2α, a class II PI3K, has an essential role in angiogenesis and vascular barrier function

Endothelial PI3K-C2α, a class II PI3K, has an essential role in angiogenesis and vascular barrier function

The p110α and p110β isoforms of PI3K play divergent roles in mammary gland development and tumorigenesis

PI3K isoform dependence of PTEN-deficient tumors can be altered by the genetic context

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