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TGF-beta Signaling Pathway

TGF-beta signaling is involved in the regulation of proliferation, differentiation and survival/or apoptosis of many cells, including glioma cells. TGF-beta acts via specific receptors activating multiple intracellular pathways resulting in phosphorylation of receptor-regulated Smad2/3 proteins that associate with the common mediator, Smad4. Such complex translocates to the nucleus, binds to DNA and regulates transcription of many genes. Furthermore, TGF-beta -activated kinase-1 (TAK1) is a component of TGF-beta signaling and activates mitogen-activated protein kinase cascades. Negative regulation of TGF-beta /Smad signaling may occur through the inhibitory Smad6/7. Increased expression of TGF-beta 1-3 correlates with a degree of malignancy of human gliomas. TGF-beta may contribute to tumor pathogenesis by direct support of tumor growth, self-renewal of glioma initiating stem cells and inhibiting of anti-tumor immunity. Inhibitors of TGF-beta signaling reduce viability and invasion of gliomas in animal models and show promises as novel, potential anti-tumor therapeutics.

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.

Raf Ras Smad7 Smad1/5/8 Smad2/3 Sos Grb2 Shc PI3K AKT mTor S6K PAK Cdc42/Rac PP2A PKC PKC Par6 Par6 Smurf1 RhoA TAK1/TAB TRAF6 MEK1/2 MKK4 MKK3/6 p38 JNK Smad4 Smad6 Co-factor JNK/p38 Smad1/5/8 ERK1/2 Transcription MAPK pathway Smad2/3 Protein phosphorylation Gene transcription Actin polymeration Stress fibers Tight junction Cell adhesion Membrane ruffling Protein synthesis Cytoplasma Nucleus TypeII Receptor Type I Receptor Type I Receptor TypeII Receptor BMP Ligands TGF-beta Ligands

TGF-beta Signaling Pathway from A to Z

AKT search result
BMP Ligands search result
Cdc42/Rac search result
Co-factor search result
ERK1/2 search result
Grb2 search result
JNK search result
JNK/p38 search result
MEK1/2 search result
MKK3/6 search result
MKK4 search result
mTor search result
p38 search result
PAK search result
Par6 search result
PI3K search result
PKC search result
Raf search result
Ras search result
RhoA search result
S6K search result
Shc search result
Smad1/5/8 search result
Smad2/3 search result
Smad4 search result
Smad6 search result
Smad7 search result
Smurf1 search result
Sos search result
TAK1/TAB TRAF6 search result
Type I Receptor search result
TypeII Receptor search result
PP2A search result
Transcription search result
MAPK pathway search result
Protein phosphorylation search result
Gene transcription search result
Actin polymeration search result
Stress fibers search result
Tight junction search result
Cell adhesion search result
Membrane ruffling search result
Protein synthesis search result
Cytoplasma search result
Nucleus search result
TGF-beta Ligands search result

Thanks to Sino Biological for providing the pathways.