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

被引：52

作者：

Beausejour, Marco ^{[1
]}

Noel, Dominique ^{[1
]}

Thibodeau, Sonya ^{[1
]}

Bouchard, Veronique ^{[1
]}

Harnois, Charlene ^{[1
]}

Beaulieu, Jean-Francois ^{[1
]}

Demers, Marie-Josee ^{[1
]}

Vachon, Pierre H. ^{[1
]}

机构：

[1] Univ Sherbrooke, Fac Med & Sci Sante, Dept Anat & Biol Cellulaire, Sherbrooke, PQ J1H 5N4, Canada

来源：

APOPTOSIS | 2012年 / 17卷 / 06期

基金：

加拿大健康研究院;

关键词：

Anoikis; Fak; HIEC; PI3-K; Src; Survival; APOPTOSIS; DEATH; MECHANISMS; MEK/ERK; KINASE; FAK; SRC; INTEGRINS; PATHWAY; DISEASE;

D O I：

10.1007/s10495-012-0713-6

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

070307 [化学生物学]; 071010 [生物化学与分子生物学];

摘要：

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.

引用

页码：566 / 578

页数：13

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