Fak/Src signaling in human intestinal epithelial cell survival and anoikis:: Differentiation State-specific uncouplin with the P13-K/Akt-1 ang MEK/Erk pathways
Fak/Src signaling in human intestinal epithelial cell survival and anoikis:: Differentiation State-specific uncouplin with the P13-K/Akt-1 ang MEK/Erk pathways
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DOI：
10.1002/jcp.21096
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发表时间：
2007-09-01
影响因子：
5.6
通讯作者：
Vachon, Pierre H.
中科院分区：
文献类型：
--
作者：
Bouchard, Vtronique;Demers, Marie-Josee;Vachon, Pierre H.
人肠上皮细胞的存活和发育受其分化状态的独特调控。在本研究中，我们分析了局灶黏附激酶(Fak)/Src信号通路在P13-K/Akt- I和丝裂原活化蛋白激酶(MEK)/细胞外调节激酶（Erk）通路中的作用。Anoikis是通过抑制β I整合素（抗体阻断）、抑制Fak（药理抑制或显性阴性突变体的过表达）或维持悬浮细胞来诱导的。分析Fak、Src、Akt- 1和Erk 1 /2的活化参数。Src、Akt- 1或Erk 1 /2的活性也被药理学抑制或显性阴性突变体的过表达阻断。我们报道：(1)在未分化和已分化的细胞中，I整合素结合活性的丧失或抑制会引起anoikis，并导致Fak、Src、Akt- 1和Erk 1 /2的下调激活；(2)无论分化状态如何，Fak的抑制同样会导致Src、Akt- 1和Erk 1 /2的抑制和下调激活；(3) Src、P]3- k /Akt- 1和MEK/Erk参与分化细胞的存活，而MEK/Erk对未分化细胞的存活没有作用；(4) I整合素结合和/或Fak活性的抑制/丧失导致Src与Fak的结合丧失，无论分化状态如何；(5) Src有助于未分化细胞中P13-K/Akt- I和MEK/Erk通路的激活，但不影响分化细胞中的P13-K/Akt- I。因此，Fak/Src信号传导到P13-K/Akt- I和MEK/Erk通路经历了分化状态特异性的解耦，最终反映了这些相同通路在肠上皮细胞存活介导中的选择性参与。
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.