title: Integrin/Fak/Src-mediated regulation of cell survival and anoikis in human intestinal epithelial crypt cells: selective engagement and roles of PI3-K isoform complexes.
abstract: In human intestinal epithelial crypt (HIEC) cells, the PI3-K/Akt-1 pathway is crucial for the promotion of cell survival and suppression of anoikis. Class I PI3-K consists of a complex formed by a catalytic (C) and regulatory (R) subunit. Three R (p85α, β, and p55γ) and four C (p110α, β, γ and δ) isoforms are known. Herein, we analyzed the expression of PI3-K isoforms in HIEC cells and determined their roles in cell survival, as well as in the β1 integrin/Fak/Src-mediated suppression of anoikis. We report that: (1) the predominant PI3-K complexes expressed by HIEC cells are p110α/p85β and p110α/p55γ; (2) the inhibition and/or siRNA-mediated expression silencing of p110α, but not that of p110β, γ or δ, results in Akt-1 down-activation and consequent apoptosis; (3) the expression silencing of p85β or p55γ, but not that of p85α, likewise induces Akt-1 down-activation and apoptosis; however, the impact of a loss of p55γ on both Akt-1 activation and cell survival is significantly greater than that from the loss of p85β; and (4) both the p110α/p85β and p110α/p55γ complexes are engaged by β1 integrin/Fak/Src signaling; however, the engagement of p110α/p85β is primarily Src-dependent, whereas that of p110α/p55γ is primarily Fak-dependent (but Src-independent). Hence, HIEC cells selectively express PI3-K isoform complexes, translating into distinct roles in Akt-1 activation and cell survival, as well as in a selective engagement by Fak and/or Src within the context of β1 integrin/Fak/Src-mediated suppression of anoikis.
authors.affiliation: Département d'anatomie et de Biologie Cellulaire, Faculté de Médecine et des Sciences de la Santé, Université de Sherbrooke, Sherbrooke, QC, Canada.
authors.forename: Marco
authors.initials: M
authors.lastname: Beauséjour
authors.forename: Dominique
authors.initials: D
authors.lastname: Noël
authors.forename: Sonya
authors.initials: S
authors.lastname: Thibodeau
authors.forename: Véronique
authors.initials: V
authors.lastname: Bouchard
authors.forename: Charlène
authors.initials: C
authors.lastname: Harnois
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Beaulieu
authors.forename: Marie-Josée
authors.initials: MJ
authors.lastname: Demers
authors.forename: Pierre H
authors.initials: PH
authors.lastname: Vachon
mesh_terms: D023102:Anoikis; D002470:Cell Survival; D004847:Epithelial Cells / Q000166:cytology* / Q000201:enzymology / Q000378:metabolism; D051417:Focal Adhesion Kinase 1 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D019012:Integrin beta1 / Q000235:genetics / Q000378:metabolism*; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000166:cytology* / Q000201:enzymology; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D019012:Integrin beta1; D007527:Isoenzymes; D019869:Phosphatidylinositol 3-Kinases; D051417:Focal Adhesion Kinase 1; C496050:PTK2 protein, human; D016392:Proto-Oncogene Proteins pp60(c-src); D051057:Proto-Oncogene Proteins c-akt