TGF-beta Signaling

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Hintergrund von TGF-beta Signaling

The transforming growth factor beta 1 (TGF-beta 1) is the first member of the TGF-beta superfamily that is comprised of a large group of proteins, including the activin/inhibin family, bone morphogenetic proteins (BMPs), growth differentiation factors (GDFs) and the TGF-beta subfamily. Members of the TGF-beta superfamily interact with a conserved family of cell surface serine/threonine-specific protein kinase receptors to activate Smad signaling cascades.

Another subfamily of the TGF-beta superfamily is GDNF (glial cell line-derived neurotrophic factor) family. The GDNF family ligands share a similar conformation with other members of the TGF-beta superfamily. However, proteins of the GDNF family do not signal through TGF-beta receptors. They signal through a multimolecular protein complex that includes the RET receptor tyrosine kinase and receptors of the GFR-alpha family.

TGF-beta superfamily of cytokines bind to receptors at the cell surface, and recruit two type I receptors and two type II receptors forming a tetrameric complex. Activated TGF-beta superfamily receptors induce a series of phosphorylation cascade, from receptor phosphorylation to subsequent phosphorylation and activation of downstream signal transducer R-Smads (receptor-activated Smads). Phosphorylated R-Smads form a heteroligomeric (often trimeric) complex with Smad4 (Co-Smad). The Smad complex is imported into the nucleus and regulates the expression of target genes by direct binding to the target gene promoter and/or through the interaction with transcriptional cofactors in a cell-type-specific manner. TGF-beta superfamily signaling controls numerous cellular responses from cell proliferation, differentiation and extracellular matrix remodelling to embryonic development in species ranging from worms to mammals.

Besides the canonical Smad-mediated TGF-beta signaling pathway, it has been shown that TGF-beta superfamily ligands can also regulate cellular or physiological processes through non-canonical pathways by the activation of other signaling molecules [e.g. Akt, MAPK (mitogen-activated protein kinase), mTOR (mammalian target of rapamycin), and Src] independent of Smad proteins, which amplifies the complexity of TGF-beta signaling.