TGF beta signaling pathway

The TGFbeta signalling pathway has an impact on a variety of cellular processes including cell proliferation, differentiation, apoptosis, growth, development, adhesion, neuronal growth, immune surveillance, tissue homeostasis and many others. Moreover, dysregulation of the normal functioning of any element is associated with pathological conditions, such as autoimmune and inflammatory diseases, cancer and cardiovascular diseases.

TGFbeta superfamily ligands transduce their signals by binding and bringing together two single-pass transmembrane receptor serine/threonine kinases called type I and II receptors. This allows the phosphorylation and activation of type I receptor by type II receptor. Once type I receptor is activated propagates the signal by phosphorylating Smad proteins, which form a heterotrimeric complex. Those complexes are then translocated into the nucleus where, in conjunction with other nuclear cofactors, regulate the transcription of target genes.

The TGF beta superfamily of ligands

The TGFbeta superfamily of cytokines can be divided in two major ligand subfamilies by sequence similarities. On one hand TGFbeta/Inhibin/Nodal/Activin subfamily and on the other hand BMP (Bone Morphogenetic Protein)/AMH (Anti-Müllerian Hormone)/GDF (Growth and Differentiation Factor) subfamily. As shown here , the members of the superfamily share a high conserved tridimensional structure

Bone morphogenetic protein

Bone morphogenetic protein

BMP-7 see Student Projects for UMass Chemistry 423 Spring 2012-4.

Bone morphogenetic protein 9

Bone morphogenetic protein 3D structures

Growth differentiation factor

Growth differentiation factor includes mentioned above Bone morphogenetic protein 9

Group:MUZIC:Myostatin

Activin

Activin

Activin A or inhibitin β chain A (ActA) is a member of the TGF-β superfamily that inhibits the proliferation of breast cancer cells. Activin interacts with activin receptors to induce phosphorylation of intracellular signalling molecules which regulate the transcription of many genes in a cell- and tissue-specific manner^[1].

TGF-beta receptor

TGF-β receptors (Transforming Growth Factor) (TGFR) are serine/threonine kinase receptors. They are involved in paracrine signaling and are found in many types of tissue. TGF-β ligands include bone morphogenetic proteins, growth and initiation factors, anti-Mullerian hormone, activin, nodal TGF-β^[2]. There are 3 types of TGFR:

• TGFR I forms heteromeric complex with TGFR II when it is bound to TGF-β. The complex transduces the TGF-β signal from the cell surface to the cytoplasm by phosphorylating proteins which regulate the transcription of genes related to cell proliferation. TGFR I has high affinity for TGF-β1 and low affinity for TGF-β2.
  
• TGFR II is a tumor suppressor transmembrane protein. TGFR II has high affinity for TGF-β1 and low affinity for TGF-β2.
  
• TGFR III is a cell-surface chondroitin sulfate / heparin sulfate proteoglycan. It acts as a reservoir of ligand for TGFRs. TGFR III has high affinity for TGF-β1, TGF-β2 and TGF-β1.2.

SMAD phosphorylation

There are five receptor regulated SMADs: SMAD1, SMAD2, SMAD3, SMAD5, and SMAD9 (sometimes referred to as SMAD8). There are essentially two intracellular pathways involving these R-SMADs. TGFβs, Activins, Nodals and some GDFs are mediated by SMAD2 and SMAD3, while BMPs, AMH and a few GDFs are mediated by SMAD1, SMAD5 and SMAD9.

• 1dd1 - CRYSTAL STRUCTURE ANALYSIS OF THE SMAD4 ACTIVE FRAGMENT
• 1dev - CRYSTAL STRUCTURE OF SMAD2 MH2 DOMAIN BOUND TO THE SMAD-BINDING DOMAIN OF SARA