Integrin beta 1 signaling is necessary for transforming growth factor-beta activation of p38MAPK and epithelial plasticity.
Integrin beta 1 signaling is necessary for transforming growth factor-beta activation of p38MAPK and epithelial plasticity.
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发表时间：
2001
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通讯作者：
N. Bhowmick;R. Zent;M. Ghiassi;M. McDonnell;H. Moses
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作者：
N. Bhowmick;R. Zent;M. Ghiassi;M. McDonnell;H. Moses
转化生长因子-β（TGF-β）可诱导乳腺上皮细胞向间充质转分化（EMT）。TGF-β介导的EMT涉及通过分别与II型和I型丝氨酸/苏氨酸激酶受体的顺序结合来刺激许多信号传导途径。整合素包括介导细胞粘附和细胞内信号传导的异源二聚体细胞外基质受体家族，因此使它们对EMT进展至关重要。根据大量证据表明TGF-β调节各种β 1整合素及其细胞外基质配体，我们研究了TGF-β和整合素信号转导途径之间的相互作用。使用诱导系统的胞质截短显性负TGF-β II型受体的表达，我们阻断TGF-β介导的生长抑制，转录激活，EMT进展。显性负性TGF-β II型受体表达抑制TGF-β信号传导至SMAD和AKT通路，但不阻断TGF-β介导的p38 MAPK活化。有趣的是，阻断整合素β（1）功能可抑制TGF-β介导的p38 MAPK活化和EMT进展。通过显性负性p38 MAPK的表达限制p38 MAPK活性也阻断了TGF-β介导的EMT。总之，TGF-β介导的p38 MAPK活化依赖于功能性整合素β（1），并且p38 MAPK活性是必需的，但不足以诱导EMT。
Transforming growth factor-beta (TGF-beta) can induce epithelial to mesenchymal transdifferentiation (EMT) in mammary epithelial cells. TGF-beta-mediated EMT involves the stimulation of a number of signaling pathways by the sequential binding of the type II and type I serine/threonine kinase receptors, respectively. Integrins comprise a family of heterodimeric extracellular matrix receptors that mediate cell adhesion and intracellular signaling, hence making them crucial for EMT progression. In light of substantial evidence indicating TGF-beta regulation of various beta(1) integrins and their extracellular matrix ligands, we examined the cross-talk between the TGF-beta and integrin signal transduction pathways. Using an inducible system for the expression of a cytoplasmically truncated dominant negative TGF-beta type II receptor, we blocked TGF-beta-mediated growth inhibition, transcriptional activation, and EMT progression. Dominant negative TGF-beta type II receptor expression inhibited TGF-beta signaling to the SMAD and AKT pathways, but did not block TGF-beta-mediated p38MAPK activation. Interestingly, blocking integrin beta(1) function inhibited TGF-beta-mediated p38MAPK activation and EMT progression. Limiting p38MAPK activity through the expression of a dominant negative-p38MAPK also blocked TGF-beta-mediated EMT. In summary, TGF-beta-mediated p38MAPK activation is dependent on functional integrin beta(1), and p38MAPK activity is required but is not sufficient to induce EMT.