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TGF-beta Signaling / TGF-beta Pathway

TGF-beta Signaling Products:     Proteins          Antibodies          ELISA Pair Sets          cDNA Clones

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. 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.

References

    1. Heldin CH, et al. (1997) TGF-beta signalling from cell membrane to nucleus through SMAD proteins. Nature. 390(6659):465-71.
    2. Derynck R, et al. (2001) TGF-beta signaling in tumor suppression and cancer progression. Nat Genet. 29(2):117-29.
    3. Kaminska B, et al. (2013) TGF beta signaling and its role in glioma pathogenesis. Adv Exp Med Biol. 986:171-87.
    4. Ikushima H, et al. (2009). Autocrine TGF-beta signaling maintains tumorigenicity of glioma-initiating cells through Sry-related HMG-box factors. Cell Stem Cell. 5(5):504-14.

TGF-beta Related Information

TGF-beta Superfamily

 

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