Thursday, March 14, 2013

Signal Transduction Pathway - The TGF-β/Smad Pathways

TGF-β/Smad pathway is like the previously mentioned JAK/STAT pathway in a way that there is direct connection between the cell surface (receptors) and the nucleus (transcription factors) instead of having a cascade of proteins.
TGF-β stands for transforming growth factor-beta. It is a protein that is involved in various cellular processes like cell differentiation, proliferation, apoptosis etc. This ligand of TGF-β superfamily is a secreted protein and it includes bone morphogenetic proteins (BMPs), growth factors, differentiation factors, activin etc.
The receptors for TGF-β family are serine/threonine kinases. These receptors are primarily composed of two types of polypeptides as type I receptor and type II receptor.

This pathway is very simple to understand. The first step in this pathway is the binding of the ligand to the receptor. This ligand first binds to a specific TGF-β type II receptor. The binding recruits TGF-β type I receptor. Being a serine/threonine kinase, type II receptor phosphorylates TGF-β type I receptor there by forming a dimer. Type I receptor in turn phosphorylates Smad proteins. The phosphorylated Smad is then translocated to the nucleus where it regulates the gene expression.

In humans, there are 42 members of TGF-β family which elicit different responses. There are seven different types of TGF-β type I receptors and five different TGF-β type II receptors. When there is interaction of TGF-β family members with their respective receptors, it leads to activation of Smads which is a family of  8 member which leads to different responses in target cells.

It is interesting to know that Smad members can also be phosphorylated by ERK and this interaction between TGF-β/Smad and ERK plays an important role in embryonic development.