Signaling Pathways That Control Gene Activity TGFβ Receptors and the Direct Activation of Smads Presented By: Todd Lindsey

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.

Release of Active TGFβ  Binding of LTBP by matrix protein thrombospondin or cell-surface integrins.  Conformational change in LTBP causes release of active TGFβ.

Smads  Smad proteins function as transcription factors in the TGFβ signaling pathway.  R-Smads (receptor-regulated)  Co-Smads  I-Smads (inhibitory)

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

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.

TGFβ Signaling Pathway  Type I TGFβ receptor phosphorylates an R- Smad (Smad3).  Phosphorylated R-Smad forms cytosolic complex with co-Smad (Smad4).

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.

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.

References  Lodish, et al. Molecular Cell Biology. W.H. Freeman and Company. New York: 