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.
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.
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DOI：
10.1007/s10495-012-0713-6
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发表时间：
2012-06
期刊：
影响因子：
7.2
通讯作者：
Vachon, Pierre H.
中科院分区：
文献类型：
--
作者：
Beausejour, Marco;Noel, Dominique;Thibodeau, Sonya;Bouchard, Veronique;Harnois, Charlene;Beaulieu, Jean-Francois;Demers, Marie-Josee;Vachon, Pierre H.
在人肠上皮隐窝（HIEC）细胞中，PI 3-K/Akt-1通路对于促进细胞存活和抑制失巢凋亡至关重要。I类PI 3-K由催化（C）和调节（R）亚基形成的复合物组成。已知有三种R（p85α、β和p55γ）和四种C（p110α、β、γ和δ）亚型。在此，我们分析了PI 3-K亚型在HIEC细胞中的表达，并确定了它们在细胞存活中的作用，以及在β1整合素/Fak/Src介导的失巢凋亡抑制中的作用。我们报告：（1）HIEC细胞主要表达的PI 3-K复合物是p110α/p85β和p110α/p55γ，（2）p110α的抑制和/或siRNA介导的表达沉默导致Akt-1的下调和凋亡，而p110β、γ或δ的抑制和/或siRNA介导的表达沉默则不会导致Akt-1的下调和凋亡;（3）p85β或p55γ的表达沉默（而非p85α的表达沉默）同样诱导Akt-1的下调和凋亡;然而，p55γ的缺失对Akt-1活化和细胞存活的影响显著大于p85β的缺失;（4）p110α/p85β和p110α/p55γ复合物都是通过β1整合素/Fak/Src信号通路参与的，但p110α/p85β的参与主要依赖于Src，而p110α/p55γ的参与主要依赖于Fak（但不依赖于Src）。因此，HIEC细胞选择性地表达PI 3-K同种型复合物，转化为Akt-1活化和细胞存活中的不同作用，以及在β1整联蛋白/Fak/Src介导的失巢凋亡抑制的背景下Fak和/或Src的选择性接合中的不同作用。
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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