TGF beta signaling pathway

R-SMAD/coSMAD complexes accumulate in the nucleus where they act as transcription factors and participate in the regulation of target gene expression.

[2] The TGF beta superfamily of ligands includes: bone morphogenetic proteins (BMPs), growth and differentiation factors (GDFs), anti-Müllerian hormone (AMH), Activin, Nodal and TGFβs.

They are involved in a multitude of cellular functions including osteogenesis, cell differentiation, anterior/posterior axis specification, growth, and homeostasis.

[7] The binding of a TGFβ family ligand causes the rotation of the receptors so that their cytoplasmic kinase domains are arranged in a catalytically favorable orientation.

The binding of the R-SMAD to the type I receptor is mediated by a zinc double finger FYVE domain containing protein.

Two such proteins that mediate the TGFβ pathway include SARA (the SMAD anchor for receptor activation) and HGS (Hepatocyte growth factor-regulated tyrosine kinase substrate).

[9] SARA orients the R-SMAD such that serine residue on its C-terminus faces the catalytic region of the Type I receptor.

Phosphorylation induces a conformational change in the MH2 domain of the R-SMAD and its subsequent dissociation from the receptor complex and SARA.

The phosphate group does not act as a docking site for coSMAD, but rather the phosphorylation opens up an amino acid stretch allowing interaction.

Bone morphogenetic proteins cause the transcription of mRNAs involved in osteogenesis, neurogenesis, and ventral mesoderm specification.

Activin causes the transcription of mRNAs involved in gonadal growth, embryo differentiation and placenta formation.

Nodal causes the transcription of mRNAs involved in left and right axis specification, mesoderm and endoderm induction.

The TGF beta signaling pathway is involved in a wide range of cellular process and subsequently is very heavily regulated.

Follistatin also is implicated in prostate cancers where mutations in its gene may preventing it from acting on activin which has anti-proliferative properties.

It is asymmetrically expressed in the left side of murine embryos and subsequently plays a role in left-right specification.

One of the downstream targets of TGF β signaling, GIPC, binds to its PDZ domain, which prevents its proteosomal degradation, which subsequently increases TGFβ activity.

[11] BMP and activin membrane bound inhibitor (BAMBI), has a similar extracellular domain as type I receptors.

They play a key role in the regulation of TGF beta signaling and are involved in negative feedback.