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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.

Beauséjour M, Noël D, Thibodeau S, Bouchard V, Harnois C, Beaulieu JF, Demers MJ, Vachon PH - Apoptosis (2012)

Bottom Line: 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.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).

View Article: PubMed Central - PubMed

Affiliation: Département d'anatomie et de Biologie Cellulaire, Faculté de Médecine et des Sciences de la Santé, Université de Sherbrooke, Sherbrooke, QC, Canada.

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.

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PI3-K isoforms and isoform complexes are selectively expressed, perform distinct roles in cell survival, and are selectively engaged by β1 integrin/Fak/Src-mediated signaling for the suppression of anoikis, in HIEC cells. Schematic drawing, which summarizes the results of the present study. p110α/p85β and p110α/p55γ are the largely predominant PI3-K isoform complexes in HIEC cells, whereas the individual isoforms p85α and p110β are expressed weakly, and p110γ and p110δ are not expressed. Only the p110α/p85β and p110α/p55γ complexes perform the critical functions of Akt-1 activation and subsequent maintenance of HIEC cell survival. However, the contributions of p110α/p55γ in Akt-1 activation and cell survival are significantly greater than those of p110α/p85β. Furthermore, p110α/p85β and p110α/p55γ are both engaged by β1 integrin/Fak/Src signaling in the suppression of anoikis; nevertheless, the engagement of p110α/p85β is primarily Src-dependent, whereas that of p110α/p55γ is primarily Fak-dependent (but Src-independent)
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Fig8: PI3-K isoforms and isoform complexes are selectively expressed, perform distinct roles in cell survival, and are selectively engaged by β1 integrin/Fak/Src-mediated signaling for the suppression of anoikis, in HIEC cells. Schematic drawing, which summarizes the results of the present study. p110α/p85β and p110α/p55γ are the largely predominant PI3-K isoform complexes in HIEC cells, whereas the individual isoforms p85α and p110β are expressed weakly, and p110γ and p110δ are not expressed. Only the p110α/p85β and p110α/p55γ complexes perform the critical functions of Akt-1 activation and subsequent maintenance of HIEC cell survival. However, the contributions of p110α/p55γ in Akt-1 activation and cell survival are significantly greater than those of p110α/p85β. Furthermore, p110α/p85β and p110α/p55γ are both engaged by β1 integrin/Fak/Src signaling in the suppression of anoikis; nevertheless, the engagement of p110α/p85β is primarily Src-dependent, whereas that of p110α/p55γ is primarily Fak-dependent (but Src-independent)

Mentions: In the present study, we investigated the expression of PI3-K isoforms and their roles in the integrin β1/Fak/Src-mediated regulation of HIEC cell survival and suppression of anoikis. Herein, we demonstrate that p110α/p85β and p110α/p55γ are the largely predominant PI3-K isoform complexes in HIEC cells, whereas the individual isoforms p85α and p110β are expressed weakly, and p110γ and p110δ are not expressed. Concordantly, only the p110α/p85β and p110α/p55γ complexes perform the critical functions of Akt-1 activation and subsequent maintenance of HIEC cell survival. However, the contributions of p110α/p55γ in Akt-1 activation and cell survival are significantly greater than those of p110α/p85β. We also provide further evidence that the maintenance of HIEC cell survival and suppression of anoikis by β1 integrins is dependent on associated Fak signaling cassettes, in which Src is recruited. To this effect, we show that the p110α/p85β and p110α/p55γ PI3-K isoform complexes are selectively engaged by such integrin/Fak/Src signaling, whereby the engagement of p110α/p85β is primarily Src-dependent and that of p110α/p55γ is primarily Fak-dependent (but Src-independent). Hence, as summarized in Fig. 8, HIEC cells selectively express PI3-K R and C subunit isoforms, which translates into a selective expression of PI3-K R/C isoform complexes, which in turn results into isoform-distinct roles in the activation of Akt-1 and the promotion of HIEC cell survival and, additionally, in their selective engagement by β1 integrin/Fak/Src signaling in the suppression of anoikis.Fig. 8


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.

Beauséjour M, Noël D, Thibodeau S, Bouchard V, Harnois C, Beaulieu JF, Demers MJ, Vachon PH - Apoptosis (2012)

PI3-K isoforms and isoform complexes are selectively expressed, perform distinct roles in cell survival, and are selectively engaged by β1 integrin/Fak/Src-mediated signaling for the suppression of anoikis, in HIEC cells. Schematic drawing, which summarizes the results of the present study. p110α/p85β and p110α/p55γ are the largely predominant PI3-K isoform complexes in HIEC cells, whereas the individual isoforms p85α and p110β are expressed weakly, and p110γ and p110δ are not expressed. Only the p110α/p85β and p110α/p55γ complexes perform the critical functions of Akt-1 activation and subsequent maintenance of HIEC cell survival. However, the contributions of p110α/p55γ in Akt-1 activation and cell survival are significantly greater than those of p110α/p85β. Furthermore, p110α/p85β and p110α/p55γ are both engaged by β1 integrin/Fak/Src signaling in the suppression of anoikis; nevertheless, the engagement of p110α/p85β is primarily Src-dependent, whereas that of p110α/p55γ is primarily Fak-dependent (but Src-independent)
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Related In: Results  -  Collection

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Fig8: PI3-K isoforms and isoform complexes are selectively expressed, perform distinct roles in cell survival, and are selectively engaged by β1 integrin/Fak/Src-mediated signaling for the suppression of anoikis, in HIEC cells. Schematic drawing, which summarizes the results of the present study. p110α/p85β and p110α/p55γ are the largely predominant PI3-K isoform complexes in HIEC cells, whereas the individual isoforms p85α and p110β are expressed weakly, and p110γ and p110δ are not expressed. Only the p110α/p85β and p110α/p55γ complexes perform the critical functions of Akt-1 activation and subsequent maintenance of HIEC cell survival. However, the contributions of p110α/p55γ in Akt-1 activation and cell survival are significantly greater than those of p110α/p85β. Furthermore, p110α/p85β and p110α/p55γ are both engaged by β1 integrin/Fak/Src signaling in the suppression of anoikis; nevertheless, the engagement of p110α/p85β is primarily Src-dependent, whereas that of p110α/p55γ is primarily Fak-dependent (but Src-independent)
Mentions: In the present study, we investigated the expression of PI3-K isoforms and their roles in the integrin β1/Fak/Src-mediated regulation of HIEC cell survival and suppression of anoikis. Herein, we demonstrate that p110α/p85β and p110α/p55γ are the largely predominant PI3-K isoform complexes in HIEC cells, whereas the individual isoforms p85α and p110β are expressed weakly, and p110γ and p110δ are not expressed. Concordantly, only the p110α/p85β and p110α/p55γ complexes perform the critical functions of Akt-1 activation and subsequent maintenance of HIEC cell survival. However, the contributions of p110α/p55γ in Akt-1 activation and cell survival are significantly greater than those of p110α/p85β. We also provide further evidence that the maintenance of HIEC cell survival and suppression of anoikis by β1 integrins is dependent on associated Fak signaling cassettes, in which Src is recruited. To this effect, we show that the p110α/p85β and p110α/p55γ PI3-K isoform complexes are selectively engaged by such integrin/Fak/Src signaling, whereby the engagement of p110α/p85β is primarily Src-dependent and that of p110α/p55γ is primarily Fak-dependent (but Src-independent). Hence, as summarized in Fig. 8, HIEC cells selectively express PI3-K R and C subunit isoforms, which translates into a selective expression of PI3-K R/C isoform complexes, which in turn results into isoform-distinct roles in the activation of Akt-1 and the promotion of HIEC cell survival and, additionally, in their selective engagement by β1 integrin/Fak/Src signaling in the suppression of anoikis.Fig. 8

Bottom Line: 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.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).

View Article: PubMed Central - PubMed

Affiliation: Département d'anatomie et de Biologie Cellulaire, Faculté de Médecine et des Sciences de la Santé, Université de Sherbrooke, Sherbrooke, QC, Canada.

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.

Show MeSH
Related in: MedlinePlus