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

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 (p85 alpha, beta, and p55 gamma) and four C (p110 alpha, beta, gamma and delta) 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 beta 1 integrin/Fak/Src-mediated suppression of anoikis. We report that: (1) the predominant PI3-K complexes expressed by HIEC cells are p110 alpha/p85 beta and p110 alpha/p55 gamma; (2) the inhibition and/or siRNA-mediated expression silencing of p110 alpha, but not that of p110 beta, gamma or delta, results in Akt-1 down-activation and consequent apoptosis; (3) the expression silencing of p85 beta or p55 gamma, but not that of p85 alpha, likewise induces Akt-1 down-activation and apoptosis; however, the impact of a loss of p55 gamma on both Akt-1 activation and cell survival is significantly greater than that from the loss of p85 beta; and (4) both the p110 alpha/p85 beta and p110 alpha/p55 gamma complexes are engaged by beta 1 integrin/Fak/Src signaling; however, the engagement of p110 alpha/p85 beta is primarily Src-dependent, whereas that of p110 alpha/p55 gamma 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 beta 1 integrin/Fak/Src-mediated suppression of anoikis.