B1 integrin/Fak/Src signaling in intestinal epithelial crypt cell survival: integration of complex regulatory mechanisms

Apoptosis. 2008 Apr;13(4):531-42. doi: 10.1007/s10495-008-0192-y.


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 beta1 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 p38beta, 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 p38beta activation; (3) MEK/Erk up-regulates Bcl-2, drives Bad phosphorylation (serine112 residue), but does not antagonize p38bactivation; (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 beta1 integrins/Fak, and is crucial for survival; and (6) beta1 integrins/Fak and/or Src regulate Bcl-2 homologs as both PI3-K/Atk-1 and MEK/Erk combined. Hence, beta1 integrin/Fak/Src signaling translates into integrated mediating functions of p38beta activation and regulation of Bcl-2 homologs by PI3-K/Akt-1 and MEK/Erk, consequently determining their requirement (or not) for survival.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anoikis / physiology*
  • Cell Survival / physiology*
  • Cells, Cultured
  • Down-Regulation
  • Focal Adhesion Kinase 1 / physiology*
  • Humans
  • Integrin beta1 / physiology*
  • Intestinal Mucosa / cytology
  • Intestinal Mucosa / physiology*
  • MAP Kinase Kinase Kinases / physiology
  • Mitogen-Activated Protein Kinase 1 / physiology
  • Mitogen-Activated Protein Kinase 11 / physiology
  • Mitogen-Activated Protein Kinase 3 / physiology
  • Oncogene Protein pp60(v-src) / physiology*
  • Phosphatidylinositol 3-Kinases / physiology
  • Proto-Oncogene Proteins c-akt / physiology
  • Proto-Oncogene Proteins c-bcl-2 / physiology
  • Signal Transduction / physiology*
  • Up-Regulation


  • Integrin beta1
  • Proto-Oncogene Proteins c-bcl-2
  • Phosphatidylinositol 3-Kinases
  • Focal Adhesion Kinase 1
  • Oncogene Protein pp60(v-src)
  • PTK2 protein, human
  • AKT1 protein, human
  • Proto-Oncogene Proteins c-akt
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 11
  • Mitogen-Activated Protein Kinase 3
  • MAP Kinase Kinase Kinases