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Specific Activation of Mitogen-activated Protein Kinase by Transforming Growth Factor- � Receptors in Lipid Rafts Is Required for

By Epithelial Cell Plasticity, Wei Zuo, Ye-guang Chen and Kunxin Luo


Transforming growth factor (TGF)- � regulates a spectrum of cellular events, including cell proliferation, differentiation, and migration. In addition to the canonical Smad pathway, TGF- � can also activate mitogen-activated protein kinase (MAPK), phosphatidylinositol 3-kinase (PI3K)/Akt, and small GTPases in a cell-specific manner. Here, we report that cholesterol depletion interfered with TGF-�–induced epithelial-mesenchymal transition (EMT) and cell migration. This interference is due to impaired activation of MAPK mediated by cholesterol-rich lipid rafts. Cholesterol-depleting agents specifically inhibited TGF-�–induced activation of extracellular signal-regulated kinase (ERK) and p38, but not Smad2/3 or Akt. Activation of ERK or p38 is required for both TGF-�–induced EMT and cell migration, whereas PI3K/Akt is necessary only for TGF-�–promoted cell migration but not for EMT. Although receptor heterocomplexes could be formed in both lipid raft and nonraft membrane compartments in response to TGF-�, receptor localization in lipid rafts, but not in clathrin-coated pits, is important for TGF-�–induced MAPK activation. Requirement of lipid rafts for MAPK activation was further confirmed by specific targeting of the intracellular domain of TGF- � type I receptor to different membrane locations. Together, our findings establish a novel link between cholesterol and EMT and cell migration, that is, cholesterol-rich lipid rafts are required for TGF-�–mediated MAPK activation, an event necessary for TGF-�–directed epithelial plasticity

Year: 2008
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