TGF-bSuperfamily.pptVIP

TGF-b Superfamily TGF-b Superfamily TGF-b signalling is regulated at all levels TGF-b Superfamily Receptor assembly dynamics Extracellular Antagonists and Membrane Level Regulation TGF-b activation Latent TGF-b activation Latent TGF-b activation Latent TGF-b activation: integrin dependent proteolysis Latent TGF-b activation: integrin-mediated cell traction Latent TGF-b activation: integrin-mediated cell traction Latent TGF-b activation: integrin-mediated cell traction Latent TGF-b activation Protease mediated latent TGF-b activation TGF-b and Angiogenesis TGF-b and Angiogenesis TGF-b and Angiogenesis TGF-b and Angiogenesis TGF-b Superfamily TGF-b Superfamily TGF-b Superfamily TGF-b Superfamily * Conserved ligands, cell-surface receptors and signaling co-receptors from C. elegans to humans 3 subfamilies: TGF-b, activin/inhibin/nodal, BMP Ligands are both homodimers or heterodimers with a set of 7 cysteines: 3 intrasubunit disulfide bonds + 1 intersubunit bond Two types cell surface receptors: serine-threonine kinases= type I and type II Receptors All type I receptors have a TTSGSGSG motif, called the GS domain 4 mammalian type II receptors: constitutively active 7 type I receptors= activin receptor like kinases 1-7 (ALK1-7) A TGF ligand signals by binding to and bringing together type I and type II receptors to form a ternary holo-complex. The assembly dynamic differs between ligands In the holo-complex, constitutively active type II kinase transphosphorylates the GS domain of type I, which then phosphorylates Smads 8 Smads, with 3 functional classes: receptor regulated Smads=R-Smad (1,5,8//2,3), co-mediator Smad= co-Smad (4), inhibitory Smad=I-Smad(6,7) 8 Smads, with 3 functional classes: receptor regulated Smads=R-Smad (1,5,8//2,3), co-mediator Smad= co-Smad (4), inhibitory Smad=I-Smad(6,7) After phopshorylation, 2 or 3 activated R-Smad di-tri-merize and form heterometric complexes with smad4.---nucleus the I-Smads negatively regulate