Human intestinal epithelial cell survival and anoikis are distinctively regulated according to the state of differentiation. In the present study, we analyzed the roles of focal adhesion kinase (Fak)/Src signaling to the P13-K/Akt- I and mitogen -activated protein kinase (MEK)/ extracellular regulated kinases (Erk) pathways, within the context of such differentiation -state distinctions. Anoikis was induced by inhibition of beta I integrins (antibody blocking), inhibition of Fak (pharmacologic inhibition or overexpression of dominant negative mutants), or by maintaining cells in suspension. Activation parameters of Fak, Src, Akt- 1, and Erk 1 /2 were analyzed. Activities of Src, Akt- 1, or Erk 1 /2 were also blocked by pharmacological inhibition or by overexpression of dominant-negative mutants. We report that: (1) the loss or inhibition of P I integrin binding activity causes anoikis and results in a down-activation of Fak, Src, Akt- 1, and Erk 1 /2 in both undifferentiated, and differentiated cells; (2) the inhibition of Fak likewise causes anoikis and a down-activation of Src, Akt- 1, and Erk 1 /2, regardless of the differentiation state; (3) Src, P]3-K/Akt- 1, and MEK/Erk contribute to the survival of differentiated cells, whereas MEK/ Erk does not play a role in the survival of undifferentiated ones; (4) the inhibition/loss of P I integrin binding and/or Fak activity results in a loss of Src engagement with Fak, regardless of the state of differentiation; and (5) Src contributes to the activation of both the P13-K/Akt- I and MEK/Erk pathways in undifferentiated cells, but does not influence P13-K/Akt- I in differentiated ones. Hence, Fak/Src signaling to the P13-K/Akt- I and MEK/Erk pathways undergoes a differentiation state-specific uncoupling which ultimately reflects upon the selective engagement of these same pathways in the mediation of intestinal epithelial cell survival.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据