β1 integrin/Fak/Src signaling in intestinal epithelial crypt cell survival:: integration of complex regulatory mechanisms

被引：62

作者：

Bouchard, Veronique ^{[1
]}

Harnois, Charlene ^{[1
]}

Demers, Marie-Josee ^{[1
]}

Thibodeau, Sonya ^{[1
]}

Laquerre, Vincent ^{[1
]}

Gauthier, Remy ^{[1
]}

Vezina, Anne ^{[1
]}

Noel, Dominique ^{[1
]}

Fujita, Naoya ^{[2
]}

Tsuruo, Takashi ^{[2
]}

Arguin, Melina ^{[1
]}

Vachon, Pierre H. ^{[1
,3
]}

机构：

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

[2] Japanese Fdn Canc Res, Ctr Canc Chemotherapy, Tokyo, Japan

[3] Univ Sherbrooke, Ctr Hosp, Themat Rech Physiopathol Digest Ctr Rech Clin Eti, Sherbrooke, PQ J1H 5N4, Canada

来源：

APOPTOSIS | 2008年 / 13卷 / 04期

基金：

加拿大健康研究院;

关键词：

Akt; anoikis; enterocyte; Fak; integrin signaling; Src;

D O I：

10.1007/s10495-008-0192-y

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

The molecular determinants which dictate survival and apoptosis/anoikis in human intestinal crypt cells remain to be fully understood. To this effect, the roles of beta 1 integrin/Fak/Src signaling to the PI3-K/Akt-1, MEK/Erk, and p38 pathways, were investigated. The regulation of six Bcl-2 homologs (Bcl-2, Mcl-1, Bcl-X-L, Bax, Bak, Bad) was likewise analyzed. We report that: (1) Anoikis causes a down-activation of Fak, Src, Akt-1 and Erk1/2, a loss of Fak-Src association, and a sustained/enhanced activation of p38 beta, which is required as apoptosis/anoikis driver; (2) PI3-K/Akt-1 up-regulates the expression of Bcl-X-L and Mcl-1, down-regulates Bax and Bak, drives Bad phosphorylation (both serine112/136 residues) and antagonizes p38 beta activation; (3) MEK/Erk up-regulates Bcl-2, drives Bad phosphorylation (serine112 residue), but does not antagonize p38 beta activation; (4) PI3-K/Akt-1 is required for survival, whereas MEK/Erk is not; (5) Src acts as a cornerstone in the engagement of both pathways by beta 1 integrins/Fak, and is crucial for survival; and (6) beta 1 integrins/Fak and/or Src regulate Bcl-2 homologs as both PI3-K/Atk-1 and MEK/Erk combined. Hence, beta 1 integrin/Fak/Src signaling translates into integrated mediating functions of p38 beta activation and regulation of Bcl-2 homologs by PI3-K/Akt-1 and MEK/Erk, consequently determining their requirement (or not) for survival.

引用

页码：531 / 542

页数：12

共 50 条

[1] Perturbations of the AKT signaling pathway in human cancer [J].