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Signaling Pathways That Control Gene Activity 14.1 - TGFβ Receptors and the Direct Activation of Smads Presented By: Todd Lindsey
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TGFβ Extracellular signaling molecules known as Transforming Growth Factor β superfamily. Secreted TGFβ is stored in extracellular matrix as inactive complex of TGFβ precursor bound to Latent TGFβ Binding Protein, or LTBP.
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Release of Active TGFβ Binding of LTBP by matrix protein thrombospondin or cell-surface integrins. Conformational change in LTBP causes release of active TGFβ.
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Smads Smad proteins function as transcription factors in the TGFβ signaling pathway. R-Smads (receptor-regulated) Co-Smads I-Smads (inhibitory)
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TGFβ Receptors Type III TGFβ receptor -Cell Surface Proteoglycan -Binds and concentrates TGFβ near surface of the cell. Type II TGFβ receptor Type I TGFβ receptor
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TGFβ Signaling Pathway TGFβ dimer induces formation of complex between Type II and Type I TGFβ receptors. Type II TGFβ receptor phosphorylates and activates Type I receptor.
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TGFβ Signaling Pathway Type I TGFβ receptor phosphorylates an R- Smad (Smad3). Phosphorylated R-Smad forms cytosolic complex with co-Smad (Smad4).
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TGFβ Signaling Pathway Smad dimer complex translocates into the nucleus. A nuclear transcription factor binds to smad complex, forming an activation complex that can bind to the target gene, activating transcription.
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Regulation of TGFβ-Smad Signaling Pathway Negative Feedback Loops ▪ Cytosolic proteins, SnoN and Ski block transcription activation by bound Smad complexes. ▪ I-Smads, such as Smad7, blocks the Type I receptors from phosphorylating R-Smad proteins.
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References Lodish, et al. Molecular Cell Biology. W.H. Freeman and Company. New York: 2004. www.whfreeman.com/lodish
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