Review
Regulation of phosphoinositide 3-kinase expression in health and disease

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Both the biology and the therapeutic potential of the phosphoinositide 3-kinase (PI3K) signalling axis have been the subject of intense investigation; however, little is known about the regulation of PI3K expression. Emerging evidence indicates that PI3K levels change in response to cellular stimulation with insulin and nuclear receptor ligands, and during various physiological and pathological processes including differentiation, regeneration, hypertension and cancer. Recently identified mechanisms that control PI3K production include increased gene copy number in cancer, and transcriptional regulation of the p110α PI3K gene by FOXO3a, NF-κB and p53, and of the PI3K regulatory subunits by STAT3, EBNA-2 and SREBP. In most instances, however, the impact of alterations in PI3K expression on PI3K signalling and disease remains to be established.

Section snippets

Dynamic regulation of phosphoinositide 3-kinase expression

The importance of the phosphoinositide 3-kinase (PI3K) signalling axis in a wide variety of normal and pathological responses is now well established. Most studies to date have focused on the acute alterations in PI3K activity induced by cell stimulation, and its impact on early downstream signalling by protein effectors of the PI3K lipids. However, emerging evidence indicates that more sustained changes in PI3K gene expression occur under various conditions, leading to persistent alterations

The PI3K family

PI3Ks generate 3-phosphorylated phosphoinositide lipids that transmit intracellular signals by binding to various protein effectors (for a review, see Ref. [1]). Mammals have genes for eight catalytic and six regulatory subunits (Table 1). The PI3Ks have been divided into three classes [1], of which the class I PI3Ks have been studied most extensively and which are the focus of this review. The expression patterns and mode of regulation of class II and III PI3Ks are less well understood (Box 1).

PI3K tissue distribution

Most PI3K subunits seem to have a broad tissue distribution, with p110γ 6, 7 and p110δ 8, 9 being highly enriched in leukocytes (Table 2). At the moment, PI3K expression patterns have only been studied at low resolution using approaches that do not enable discrimination between the different cell types in a tissue. In addition, high quality antibodies to PI3K subunits, especially antibodies that are validated for use in immunohistochemistry, are not available. In the rare instances in which

Dynamic regulation of the ratio of p85 to p110 subunits – a mechanism to regulate PI3K activity?

Under basal conditions, class IA PI3Ks are thought to exist mainly as obligate heterodimers, with the regulatory and catalytic subunits constitutively bound to each other. This model is based on the notion that the p85 and p110 proteins bind each other extremely tightly, an interaction that can withstand high concentrations of salt, urea or detergent 15, 16. Furthermore, both the catalytic [17] and the regulatory subunits 18, 19 seem to be unstable as monomers. Together, this is expected to

Regulation of class I PI3K gene expression

The investigation of molecular mechanisms controlling PI3K gene regulation and expression has only recently been initiated, with promoter analyses for PIK3CA 10, 42, 43 and PIK3CG [44] and the identification of transcription factors that control expression of p110α 10, 42, 43, p55α 45, 46, p50α [45] and p55γ [47] and identification of micro-RNAs that negatively regulate p85α [48] and p85β mRNA levels [49]. Emerging evidence indicates that PI3K expression can be modulated during cell

Concluding remarks

Under basal (i.e. unstimulated) conditions, the expression of the PI3K regulatory and catalytic subunits seems to fall mainly under transcriptional control, with mRNA levels correlating well with protein levels, leading to equal amounts of p85 and p110 protein in cells [20]. Stimuli and transcription factors that induce PI3K gene expression have recently been identified. Some stimuli (such as a CB1 antagonist and estradiol) can induce an immediate, initial increase in PI3K activity owing to

Acknowledgements

We thank Antonio Bilancio, Jan Domin, Emilio Hirsch, Klaus Okkenhaug and members of the Cell Signalling group for critical reading of the manuscript. Personal support was from the Amsterdam Medical Centre and the University of Groningen, The Netherlands (to K.K.), Roche Research Foundation, Switzerland, Janggen-Pöhn Stiftung, Switzerland and Uarda-Frutiger Fonds, Switzerland (to B.G.), and the Ludwig Institute for Cancer Research (to K.K., B.G., B.V.). Work in the B.V. laboratory was supported

References (127)

  • A. Kallin

    SREBP1 regulates the expression of heme oxygenase 1 and the phosphatidylinositol-3 kinase regulatory subunit p55γ

    J. Lipid Res.

    (2007)
  • T. Okamoto

    Differential regulation of the regulatory subunits for phosphatidylinositol 3-kinase in response to motor nerve injury

    Brain Res. Mol. Brain Res.

    (2004)
  • L. Bi

    Proliferative defect and embryonic lethality in mice homozygous for a deletion in the p110α subunit of phosphoinositide 3-kinase

    J. Biol. Chem.

    (1999)
  • K.D. Puri

    The role of endothelial PI3Kγ activity in neutrophil trafficking

    Blood

    (2005)
  • P. Sujobert

    Essential role for the p110δ isoform in phosphoinositide 3-kinase activation and cell proliferation in acute myeloid leukemia

    Blood

    (2005)
  • G. Alloatti

    Phosphoinositide 3-kinase γ controls autonomic regulation of the mouse heart through Gi-independent downregulation of cAMP level

    FEBS Lett.

    (2005)
  • E. Patrucco

    PI3Kγ modulates the cardiac response to chronic pressure overload by distinct kinase-dependent and -independent effects

    Cell

    (2004)
  • F.B. Hickey et al.

    BCR-ABL regulates phosphatidylinositol 3-Kinase-p110γ transcription and activation and is required for proliferation and drug resistance

    J. Biol. Chem.

    (2006)
  • K. Inukai

    A novel 55-kDa regulatory subunit for phosphatidylinositol 3-kinase structurally similar to p55PIK Is generated by alternative splicing of the p85α gene

    J. Biol. Chem.

    (1996)
  • K. Inukai

    p85α gene generates three isoforms of regulatory subunit for phosphatidylinositol 3-kinase (PI 3-Kinase), p50α, p55α, and p85α, with different PI 3-kinase activity elevating responses to insulin

    J. Biol. Chem.

    (1997)
  • S. Banerjee

    17α-estradiol-induced VEGF-A expression in rat pituitary tumor cells is mediated through ER independent but PI3K-Akt dependent signaling pathway

    Biochem. Biophys. Res. Commun.

    (2003)
  • B. Vanhaesebroeck

    Synthesis and function of 3-phosphorylated inositol lipids

    Annu. Rev. Biochem.

    (2001)
  • J. Guillermet-Guibert

    The p110β isoform of phosphoinositide 3-kinase signals downstream of G protein-coupled receptors and is functionally redundant with p110γ

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

    (2008)
  • M. Barbier

    Tumour biology. Weakening link to colorectal cancer?

    Nature

    (2001)
  • Z. Li

    Roles of PLC-2 and -3 and PI3K in chemoattractant-mediated signal transduction

    Science

    (2000)
  • B. Vanhaesebroeck

    p110δ, a novel phosphoinositide 3-kinase in leukocytes

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

    (1997)
  • N. Yang

    Transcriptional regulation of PIK3CA oncogene by NF-κB in ovarian cancer microenvironment

    PLoS ONE

    (2008)
  • S.S. El Sheikh

    Topographical expression of class IA and class II phosphoinositide 3-kinase enzymes in normal human tissues is consistent with a role in differentiation

    BMC Clin. Pathol.

    (2003)
  • L.C. Foukas

    Critical role for the p110α phosphoinositide-3-OH kinase in growth and metabolic regulation

    Nature

    (2006)
  • K. Okkenhaug

    Impaired B and T cell antigen receptor signaling in p110δ PI 3-kinase mutant mice

    Science

    (2002)
  • B.J. Eickholt

    Control of axonal growth and regeneration of sensory neurons by the p110δ PI 3-Kinase

    PLoS One

    (2007)
  • M.J. Fry

    Purification and characterization of a phosphatidylinositol 3-kinase complex from bovine brain by using phosphopeptide affinity columns

    Biochem. J.

    (1992)
  • A. Kazlauskas et al.

    Phosphorylation of the PDGF receptor β subunit creates a tight binding site for phosphatidylinositol 3 kinase

    EMBO J.

    (1990)
  • J. Yu

    Regulation of the p85/p110 phosphatidylinositol 3′-kinase: stabilization and inhibition of the p110α catalytic subunit by the p85 regulatory subunit

    Mol. Cell. Biol.

    (1998)
  • S.M. Brachmann

    Role of phosphoinositide 3-kinase regulatory isoforms in development and actin rearrangement

    Mol. Cell. Biol.

    (2005)
  • J.J. Zhao

    The p110α isoform of PI3K is essential for proper growth factor signaling and oncogenic transformation

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

    (2006)
  • B. Geering

    Class IA phosphoinositide 3-kinases are obligate p85-p110 heterodimers

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

    (2007)
  • J. Luo et al.

    The negative regulation of phosphoinositide 3-kinase signaling by p85 and it's implication in cancer

    Cell Cycle

    (2005)
  • D. Chen

    p50α/p55α phosphoinositide 3-kinase knockout mice exhibit enhanced insulin sensitivity

    Mol. Cell. Biol.

    (2004)
  • D.A. Fruman

    Hypoglycaemia, liver necrosis and perinatal death in mice lacking all isoforms of phosphoinositide 3-kinase p85 α

    Nat. Genet.

    (2000)
  • Y. Terauchi

    Increased insulin sensitivity and hypoglycaemia in mice lacking the p85 α subunit of phosphoinositide 3-kinase

    Nat. Genet.

    (1999)
  • K. Ueki

    Increased insulin sensitivity in mice lacking p85β subunit of phosphoinositide 3-kinase

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

    (2002)
  • B. Geering

    Regulation of class IA PI3Ks: is there a role for monomeric PI3K subunits? Biochem

    Soc. Trans.

    (2007)
  • J.P. del Rincon

    Growth hormone regulation of p85α expression and phosphoinositide 3-kinase activity in adipose tissue: mechanism for growth hormone-mediated insulin resistance

    Diabetes

    (2007)
  • J. Rieusset

    The expression of the p85α subunit of phosphatidylinositol 3-kinase is induced by activation of the peroxisome proliferator-activated receptor γ in human adipocytes

    Diabetologia

    (2001)
  • F. Andreelli

    Defective regulation of phosphatidylinositol-3-kinase gene expression in skeletal muscle and adipose tissue of non-insulin-dependent diabetes mellitus patients

    Diabetologia

    (1999)
  • F. Andreelli

    Regulation of gene expression during severe caloric restriction: lack of induction of p85 α phosphatidylinositol 3-kinase mRNA in skeletal muscle of patients with type II (non-insulin-dependent) diabetes mellitus

    Diabetologia

    (2000)
  • P.H. Ducluzeau

    Regulation by insulin of gene expression in human skeletal muscle and adipose tissue. Evidence for specific defects in type 2 diabetes

    Diabetes

    (2001)
  • J. Bastien

    The phosphoinositide 3-kinase/Akt pathway is essential for the retinoic acid-induced differentiation of F9 cells

    Oncogene

    (2006)
  • I. Esposito

    The cannabinoid CB1 receptor antagonist Rimonabant stimulates 2-deoxyglucose uptake in skeletal muscle cells by regulating phosphatidylinositol-3-kinase activity

    Mol. Pharmacol.

    (2008)
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