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Gene Review

PI3  -  peptidase inhibitor 3, skin-derived

Homo sapiens

Synonyms: ELAFIN, ESI, Elafin, Elastase-specific inhibitor, PI-3, ...
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Disease relevance of PI3


Psychiatry related information on PI3

  • ESI Cognitive Orientation Toward Spirituality significantly correlated with Complex Partial Epileptic-like Signs but it was not a significant predictor in regression analyses [6].

High impact information on PI3

  • Here we report that, in addition to PI-3' kinase activity, anti-phosphotyrosine (alpha-P-tyr) immunoprecipitates from platelet-derived growth factor (PDGF)-stimulated smooth muscle cells (SMC) contain lipid kinase activities that utilize the substrates phosphatidylinositol-4-phosphate (PI-4-P) and phosphatidylinositol-4,5-bisphosphate (PI-4,5-P2) [7].
  • These results demonstrate that the PI 3-kinase-Akt signaling pathway, in concert with FRAP/mTOR, induces the phosphorylation of 4E-BP1 [8].
  • Here we demonstrate in CD4(+) T cells that CpG DNA directly enhances proliferation, prevents anergy, and augments humoral responses to a T cell-dependent antigen by a Myeloid differentiation primary-response protein 88 (MyD88) and Phosphatidylinositol 3-kinase (PI-3 kinase)-dependent pathway [9].
  • To investigate this, we showed that wire-induced endothelial denudation of the carotid artery is associated with transient elevation in elastase activity and confirmed that this is abolished in transgenic mice overexpressing the serine elastase inhibitor, elafin, targeted to the cardiovascular system [10].
  • To distinguish the transgene from endogenous elafin, constructs were made incorporating a FLAG sequence; the COOH-terminus FLAG-tagged elafin construct produced a stable, functionally active gene product and was used to create transgenic mice [11].

Chemical compound and disease context of PI3


Biological context of PI3


Anatomical context of PI3


Associations of PI3 with chemical compounds

  • The elafin molecule, a 6.0 kD inhibitor of serine proteinases shows homology with mucus proteinase inhibitor [17].
  • In contrast, progesterone treatment has no direct effect on elafin mRNA expression [18].
  • This insulin resistance was associated with impaired insulin receptor substrate (IRS)-2-associated phosphatidylinositol 3' (PI3) kinase activation and IRS-2 tyrosine phosphorylation as well as significantly decreased protein kinase C (PKC)-zeta/lambda activation in response to insulin [23].
  • Furthermore, treatment with 10 microM of phosphatidylinositol 3 (PI3) kinase inhibitor, LY294002, abrogates HGF-induced cell scattering of SHIP-2-overexpressing cells but not parental HEK293 cells, suggesting that a balance between PI3 kinase and SHIP is important for cell motility [24].
  • Thus, engagement of membrane estrogen receptors results in rapid endothelial NO release through a PI3-kinase-Akt-dependent pathway [25].
  • NE in excess was shown to strongly diminish the ability of elafin to bind lipopolysaccharide (LPS) and its capacity to be immobilized by transglutamination [26].

Physical interactions of PI3


Enzymatic interactions of PI3

  • Correspondingly, the association between phosphatidyl-inositol 3 (PI3) kinase and phosphorylated IRS-1 was reduced in PNET1 compared with PNET2 cells [29].
  • Artemis protein is phosphorylated in a PI3-like kinase-dependent manner after either IR or a number of other DNA damaging treatments including etoposide, but SCIDA cells are not hypersensitive to treatment with etoposide [30].

Co-localisations of PI3

  • Double staining demonstrated that elafin was co-localized with tTG [31].

Regulatory relationships of PI3


Other interactions of PI3

  • In addition, we show that interleukin-1 beta and tumor necrosis factor induce significant SLPI expression and are major inducers of elafin/pre-elafin expression [20].
  • The thermodynamic and kinetic constants of the reactions of ESI with human neutrophil elastase and with porcine pancreatic elastase show that ESI is a fast-acting inhibitor [16].
  • VEGF has been shown to mediate this additional function, at least in part through the induction of bcl-2 and the activation of the PI3 kinase-Akt/PKB signaling pathway [36].
  • Transfection with tumor suppressor PTEN cDNA into HT1080 and constitutively active PI 3-kinase-CAAX cDNA into MCH603 cells, respectively, resulted in several interesting and novel observations [37].
  • PTEN lipid phosphatase degrades PIP3 and negatively regulates Akt, whereas this is activated by EGFR through PI3 [38].

Analytical, diagnostic and therapeutic context of PI3


  1. Adenoviral gene delivery of elafin and secretory leukocyte protease inhibitor attenuates NF-kappa B-dependent inflammatory responses of human endothelial cells and macrophages to atherogenic stimuli. Henriksen, P.A., Hitt, M., Xing, Z., Wang, J., Haslett, C., Riemersma, R.A., Webb, D.J., Kotelevtsev, Y.V., Sallenave, J.M. J. Immunol. (2004) [Pubmed]
  2. Secretion of mucus proteinase inhibitor and elafin by Clara cell and type II pneumocyte cell lines. Sallenave, J.M., Silva, A., Marsden, M.E., Ryle, A.P. Am. J. Respir. Cell Mol. Biol. (1993) [Pubmed]
  3. Elafin-overexpressing mice have improved cardiac function after myocardial infarction. Ohta, K., Nakajima, T., Cheah, A.Y., Zaidi, S.H., Kaviani, N., Dawood, F., You, X.M., Liu, P., Husain, M., Rabinovitch, M. Am. J. Physiol. Heart Circ. Physiol. (2004) [Pubmed]
  4. Measles virus contact with T cells impedes cytoskeletal remodeling associated with spreading, polarization, and CD3 clustering. Müller, N., Avota, E., Schneider-Schaulies, J., Harms, H., Krohne, G., Schneider-Schaulies, S. Traffic (2006) [Pubmed]
  5. Molecular targeting therapy for pancreatic cancer. Xiong, H.Q. Cancer Chemother. Pharmacol. (2004) [Pubmed]
  6. Spirituality and complex partial epileptic-like signs. MacDonald, D.A., Holland, D. Psychological reports. (2002) [Pubmed]
  7. PDGF-dependent tyrosine phosphorylation stimulates production of novel polyphosphoinositides in intact cells. Auger, K.R., Serunian, L.A., Soltoff, S.P., Libby, P., Cantley, L.C. Cell (1989) [Pubmed]
  8. 4E-BP1, a repressor of mRNA translation, is phosphorylated and inactivated by the Akt(PKB) signaling pathway. Gingras, A.C., Kennedy, S.G., O'Leary, M.A., Sonenberg, N., Hay, N. Genes Dev. (1998) [Pubmed]
  9. The Adaptor Molecule MyD88 Activates PI-3 Kinase Signaling in CD4(+) T Cells and Enables CpG Oligodeoxynucleotide-Mediated Costimulation. Gelman, A.E., Larosa, D.F., Zhang, J., Walsh, P.T., Choi, Y., Sunyer, J.O., Turka, L.A. Immunity (2006) [Pubmed]
  10. Suppressed smooth muscle proliferation and inflammatory cell invasion after arterial injury in elafin-overexpressing mice. Zaidi, S.H., You, X.M., Ciura, S., O'Blenes, S., Husain, M., Rabinovitch, M. J. Clin. Invest. (2000) [Pubmed]
  11. Targeted overexpression of elafin protects mice against cardiac dysfunction and mortality following viral myocarditis. Zaidi, S.H., Hui, C.C., Cheah, A.Y., You, X.M., Husain, M., Rabinovitch, M. J. Clin. Invest. (1999) [Pubmed]
  12. MHC-I-induced apoptosis in human B-lymphoma cells is dependent on protein tyrosine and serine/threonine kinases. Pedersen, A.E., Bregenholt, S., Johansen, B., Skov, S., Claesson, M.H. Exp. Cell Res. (1999) [Pubmed]
  13. Differential effects of detergents on keratinocyte gene expression. van Ruissen, F., Le, M., Carroll, J.M., van der Valk, P.G., Schalkwijk, J. J. Invest. Dermatol. (1998) [Pubmed]
  14. Levels of skin-derived antileukoproteinase (SKALP)/elafin in serum correlate with disease activity during treatment of severe psoriasis with cyclosporin A. Alkemade, H.A., de Jongh, G.J., Arnold, W.P., van de Kerkhof, P.C., Schalkwijk, J. J. Invest. Dermatol. (1995) [Pubmed]
  15. Molecular resolution and fragmentation of fulvic acid by electrospray ionization/multistage tandem mass spectrometry. Leenheer, J.A., Rostad, C.E., Gates, P.M., Furlong, E.T., Ferrer, I. Anal. Chem. (2001) [Pubmed]
  16. Purification and characterization of elastase-specific inhibitor. Sequence homology with mucus proteinase inhibitor. Sallenave, J.M., Ryle, A.P. Biol. Chem. Hoppe-Seyler (1991) [Pubmed]
  17. Characterization and gene sequence of the precursor of elafin, an elastase-specific inhibitor in bronchial secretions. Sallenave, J.M., Silva, A. Am. J. Respir. Cell Mol. Biol. (1993) [Pubmed]
  18. Differential regulation of secretory leukocyte protease inhibitor and elafin by progesterone. King, A.E., Morgan, K., Sallenave, J.M., Kelly, R.W. Biochem. Biophys. Res. Commun. (2003) [Pubmed]
  19. Protein kinase B/Akt-mediated phosphorylation promotes nuclear exclusion of the winged helix transcription factor FKHR1. Biggs, W.H., Meisenhelder, J., Hunter, T., Cavenee, W.K., Arden, K.C. Proc. Natl. Acad. Sci. U.S.A. (1999) [Pubmed]
  20. Regulation of secretory leukocyte proteinase inhibitor (SLPI) and elastase-specific inhibitor (ESI/elafin) in human airway epithelial cells by cytokines and neutrophilic enzymes. Sallenave, J.M., Shulmann, J., Crossley, J., Jordana, M., Gauldie, J. Am. J. Respir. Cell Mol. Biol. (1994) [Pubmed]
  21. Skin-derived antileukoproteinase (SKALP), an elastase inhibitor from human keratinocytes. Purification and biochemical properties. Schalkwijk, J., de Roo, C., de Jongh, G.J. Biochim. Biophys. Acta (1991) [Pubmed]
  22. Elafin and its precursor trappin-2 still inhibit neutrophil serine proteinases when they are covalently bound to extracellular matrix proteins by tissue transglutaminase. Guyot, N., Zani, M.L., Maurel, M.C., Dallet-Choisy, S., Moreau, T. Biochemistry (2005) [Pubmed]
  23. Insulin resistance, defective insulin receptor substrate 2-associated phosphatidylinositol-3' kinase activation, and impaired atypical protein kinase C (zeta/lambda) activation in myotubes from obese patients with impaired glucose tolerance. Vollenweider, P., Ménard, B., Nicod, P. Diabetes (2002) [Pubmed]
  24. The SH2-domian-containing inositol 5-phosphatase (SHIP)-2 binds to c-Met directly via tyrosine residue 1356 and involves hepatocyte growth factor (HGF)-induced lamellipodium formation, cell scattering and cell spreading. Koch, A., Mancini, A., El Bounkari, O., Tamura, T. Oncogene (2005) [Pubmed]
  25. Membrane estrogen receptor engagement activates endothelial nitric oxide synthase via the PI3-kinase-Akt pathway in human endothelial cells. Haynes, M.P., Sinha, D., Russell, K.S., Collinge, M., Fulton, D., Morales-Ruiz, M., Sessa, W.C., Bender, J.R. Circ. Res. (2000) [Pubmed]
  26. Elafin, an elastase-specific inhibitor, is cleaved by its cognate enzyme neutrophil elastase in sputum from individuals with cystic fibrosis. Guyot, N., Butler, M.W., McNally, P., Weldon, S., Greene, C.M., Levine, R.L., O'Neill, S.J., Taggart, C.C., McElvaney, N.G. J. Biol. Chem. (2008) [Pubmed]
  27. Dissecting the basis of nongenomic activation of endothelial nitric oxide synthase by estradiol: role of ERalpha domains with known nuclear functions. Chambliss, K.L., Simon, L., Yuhanna, I.S., Mineo, C., Shaul, P.W. Mol. Endocrinol. (2005) [Pubmed]
  28. Skin-derived antileukoproteinase (SKALP) and epidermal fatty acid-binding protein (E-FABP): two novel markers of the psoriatic phenotype that respond differentially to topical steroid. Kuijpers, A.L., Bergers, M., Siegenthaler, G., Zeeuwen, P.L., van de Kerkhof, P.C., Schalkwijk, J. Acta Derm. Venereol. (1997) [Pubmed]
  29. Insulin-induced differentiation and modulation of neuronal thread protein expression in primitive neuroectodermal tumor cells is linked to phosphorylation of insulin receptor substrate-1. Xu, Y.Y., Bhavani, K., Wands, J.R., de la Monte, S.M. J. Mol. Neurosci. (1995) [Pubmed]
  30. Artemis deficiency confers a DNA double-strand break repair defect and Artemis phosphorylation status is altered by DNA damage and cell cycle progression. Wang, J., Pluth, J.M., Cooper, P.K., Cowan, M.J., Chen, D.J., Yannone, S.M. DNA Repair (Amst.) (2005) [Pubmed]
  31. Expression of tissue transglutaminase and elafin in human coronary artery: implication for plaque instability. Sumi, Y., Inoue, N., Azumi, H., Seno, T., Okuda, M., Hirata, K., Kawashima, S., Hayashi, Y., Itoh, H., Yokoyama, M. Atherosclerosis (2002) [Pubmed]
  32. PTEN gene transfer in human malignant glioma: sensitization to irradiation and CD95L-induced apoptosis. Wick, W., Furnari, F.B., Naumann, U., Cavenee, W.K., Weller, M. Oncogene (1999) [Pubmed]
  33. PTEN expression elicited by EGR-1 transcription factor in calyculin A-induced apoptotic cells. Okamura, H., Yoshida, K., Morimoto, H., Haneji, T. J. Cell. Biochem. (2005) [Pubmed]
  34. EGFR enhances Survivin expression through the phosphoinositide 3 (PI-3) kinase signaling pathway. Wang, Q., Greene, M.I. Exp. Mol. Pathol. (2005) [Pubmed]
  35. Expression of phosphatidylinositol 3-kinase during EGF-stimulated wound repair in rabbit corneal epithelium. Zhang, Y., Liou, G.I., Gulati, A.K., Akhtar, R.A. Invest. Ophthalmol. Vis. Sci. (1999) [Pubmed]
  36. Marked induction of the IAP family antiapoptotic proteins survivin and XIAP by VEGF in vascular endothelial cells. Tran, J., Rak, J., Sheehan, C., Saibil, S.D., LaCasse, E., Korneluk, R.G., Kerbel, R.S. Biochem. Biophys. Res. Commun. (1999) [Pubmed]
  37. Role of phosphoinositide 3-kinase in the aggressive tumor growth of HT1080 human fibrosarcoma cells. Gupta, S., Stuffrein, S., Plattner, R., Tencati, M., Gray, C., Whang, Y.E., Stanbridge, E.J. Mol. Cell. Biol. (2001) [Pubmed]
  38. PAkt, cyclin D1 and p27/Kip.1 in glioblastomas with and without EGFR amplification and PTEN mutation. Fiano, V., Ghimenti, C., Imarisio, S., Silengo, L., Schiffer, D. Anticancer Res. (2004) [Pubmed]
  39. Cellular association of antiproteases in lavages from ventilated preterm human neonates. Griese, M., Schredl, M., Hochstrasser, K., Gebhard, W. Am. J. Respir. Crit. Care Med. (1997) [Pubmed]
  40. Human alveolar macrophages express elafin and secretory leukocyte protease inhibitor. Mihaila, A., Tremblay, G.M. Z. Naturforsch., C, J. Biosci. (2001) [Pubmed]
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