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

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Abstract

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 β1 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-XL, 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 p38β, which is required as apoptosis/anoikis driver; (2) PI3-K/Akt-1 up-regulates the expression of Bcl-XL and Mcl-1, down-regulates Bax and Bak, drives Bad phosphorylation (both serine112/136 residues) and antagonizes p38β activation; (3) MEK/Erk up-regulates Bcl-2, drives Bad phosphorylation (serine112 residue), but does not antagonize p38β 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 β1 integrins/Fak, and is crucial for survival; and (6) β1 integrins/Fak and/or Src regulate Bcl-2 homologs as both PI3-K/Atk-1 and MEK/Erk combined. Hence, β1 integrin/Fak/Src signaling translates into integrated mediating functions of p38β activation and regulation of Bcl-2 homologs by PI3-K/Akt-1 and MEK/Erk, consequently determining their requirement (or not) for survival.

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Acknowledgements

The authors thank Drs. J. Landry (Centre de Recherche en Cancérologie de l’Université Laval, C.H.U.L., QC, Canada), J.T. Parsons (Health Science Center, University of Virginia, Charlottesville, VA, USA), J.C. Reed (The Burnham Institute, LaJolla, CA, USA) and E. Ruoslahti (The Burnham Institute, LaJolla, CA) for the kind gift of tools. Financial support: Canadian Institutes of Health Research (CIHR) and The Cancer Research Society Inc. P.H.V. is a Chercheur-Boursier Sénior du Fonds de la Recherche en Santé du Québec (FRSQ) and a Chercheur de la Fondation Canadienne pour l’Innovation (FCI/CFI).

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Authors and Affiliations

  1. Département d’Anatomie et de Biologie Cellulaire, Faculté de Médecine et des Sciences de la Santé, Université de Sherbrooke, Sherbrooke, QC, Canada, J1H5N4

    Véronique Bouchard, Charlène Harnois, Marie-Josée Demers, Sonya Thibodeau, Vincent Laquerre, Rémy Gauthier, Anne Vézina, Dominique Noël, Mélina Arguin & Pierre H. Vachon

  2. The Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo, Japan

    Naoya Fujita & Takashi Tsuruo

  3. Thématique de Recherche en Physiopathologie Digestive du Centre de Recherches Cliniques Étienne-Lebel, Centre Hospitalier Universitaire de Sherbrooke, Campus Fleurimont, Sherbrooke, QC, Canada, J1H5N4

    Pierre H. Vachon

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  1. Véronique Bouchard
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Correspondence to Pierre H. Vachon.

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Bouchard, V., Harnois, C., Demers, MJ. et al. β1 integrin/Fak/Src signaling in intestinal epithelial crypt cell survival: integration of complex regulatory mechanisms. Apoptosis 13, 531–542 (2008). https://doi.org/10.1007/s10495-008-0192-y

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