Signaling Pathways Signaling Pathways That Control Gene That Control Gene

ActivityActivity

14.1 - TGF14.1 - TGFββ Receptors and Receptors and the Direct Activation of the Direct Activation of

SmadsSmadsPresented By: Todd LindseyPresented By: Todd Lindsey

TGFTGFββ Extracellular signaling molecules Extracellular signaling molecules

known as Transforming Growth known as Transforming Growth Factor Factor ββ superfamily. superfamily.

Secreted TGFSecreted TGFββ is stored in is stored in extracellular matrix as inactive extracellular matrix as inactive complex of TGFcomplex of TGFββ precursor bound precursor bound to Latent TGFto Latent TGFββ Binding Protein, or Binding Protein, or LTBP.LTBP.

Release of Active Release of Active TGFTGFββ

Binding of LTBP by matrix Binding of LTBP by matrix protein thrombospondin or cell-protein thrombospondin or cell-surface integrins.surface integrins.

Conformational change in LTBP Conformational change in LTBP causes release of active TGFcauses release of active TGFββ..

SmadsSmads

Smad proteins function as Smad proteins function as transcription factors in the TGFtranscription factors in the TGFββ signaling pathway.signaling pathway.

R-Smads (receptor-regulated)R-Smads (receptor-regulated) Co-SmadsCo-Smads I-Smads (inhibitory)I-Smads (inhibitory)

TGFTGFββ ReceptorsReceptors

Type III TGFType III TGFββ receptor receptor-Cell Surface Proteoglycan -Cell Surface Proteoglycan -Binds and concentrates TGF-Binds and concentrates TGFββ near near surface of the cell.surface of the cell.

Type II TGFType II TGFββ receptor receptor Type I TGFType I TGFββ receptor receptor

TGFTGFββ Signaling Signaling PathwayPathway

TGFTGFββ dimer induces dimer induces formation of complex formation of complex between Type II and between Type II and Type I TGFType I TGFββ receptors.receptors.

Type II TGFType II TGFββ receptor receptor phosphorylates and phosphorylates and activates Type I activates Type I receptor.receptor.

TGFTGFββ Signaling Signaling PathwayPathway

Type I TGFType I TGFββ receptor receptor phosphorylates an R-phosphorylates an R-Smad (Smad3).Smad (Smad3).

Phosphorylated R-Phosphorylated R-Smad forms cytosolic Smad forms cytosolic complex with co-complex with co-Smad (Smad4).Smad (Smad4).

TGFTGFββ Signaling Signaling PathwayPathway

Smad dimer complex Smad dimer complex translocates into the translocates into the nucleus.nucleus.

A nuclear A nuclear transcription factor transcription factor binds to smad binds to smad complex, forming an complex, forming an activation complex activation complex that can bind to the that can bind to the target gene, target gene, activating activating transcription.transcription.

Regulation of TGFRegulation of TGFββ--Smad Signaling Smad Signaling PathwayPathway Negative Feedback LoopsNegative Feedback Loops

▪▪ Cytosolic proteins, Cytosolic proteins, SnoNSnoN and and Ski Ski block transcription activation by block transcription activation by bound Smad complexes.bound Smad complexes.

▪ ▪ I-Smads, such as Smad7, blocks I-Smads, such as Smad7, blocks the Type I receptors from the Type I receptors from phosphorylating R-Smad proteins.phosphorylating R-Smad proteins.

ReferencesReferences

Lodish, et al. Lodish, et al. Molecular Cell Molecular Cell BiologyBiology. W.H. Freeman and . W.H. Freeman and Company. New York: 2004.Company. New York: 2004.

www.whfreeman.com/lodishwww.whfreeman.com/lodish