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TGF_beta
Presented by Sanaa ELatfihy
The transforming growth factor (TGF-beta)
Introduction
TGF-βbeta super family is fundamental in regulation of various biological processes, such as growth, development, tissue homeostasis and regulation of the immune system.
The TGF-betaβ superfamily is composed of a large group of proteins, including the activin/inhibin family, etc.
Beta-type subfamily growth factors are homodimeric or heterodimeric polypeptides with multiple regulatory properties.
Transforming Growth Factor-βbeta (TGF-betaβ) is a key player in cell proliferation, differentiation and apoptosis.
TGF-beta
TGF-beta synthesis and activation
Figure 1:TGF-β synthesis and activation.
The TGF-b type I
The TGF-b type I
-The type I receptor includes a 30- 20 amino acid
glycine-serine rich regulatory domain in cytoplasmic part, known as the GS box (GS, purple).
-GS region of the receptor is required to be phosphorylated to completely activate TβRI.
The TGF-b type II
The TGF-b type II
-The TGF-b type I and type II receptors, TbR-I and TbR-II.
-The extracellular domains (ECDs) of TbR-I and TbR-II are small (101 and 136 residues,respectively
- Transmembrane domain (TMDs)
-Cytoplasmic serine-threonine kinase domains (S/TKD).
-T-beta-βRII contains 10 bp polyadenine repeat
in the coding region of the extracellular domain.
Signaling pathway
Signaling Pathways
Canonical signaling
Canonical signaling
The SMAD are the only known latent cytoplasmic transcription factors that become directly activated by serine phosphorylation at their cognate receptors. SMADs can be classified into 3 groups based on their function:
-The receptor-regulated SMADs (R-SMADs), SMAD1, SMAD2, SMAD3, SMAD5 and SMAD8;
-The common SMAD (Co-SMAD), SMAD4 (NOT receptor substrates)
-Inhibitory SMADs (I-SMADs), SMAD6 and SMAD7.
R-SMADs and Co-SMAD consist of a conserved MH1 N-terminal domain (Mad-homology-1) and C-terminal MH2 domain (Mad-homology-2), which are connected by a ’linker’ segment.
The C-terminal domain promotes transcriptional activity, when fused to a heterologous DNA binding domain. On the contrary, I-SMADs contain only the highly conserved MH2 domain.
The MH1 domain is responsible for binding to DNA; however, the MH2 domain contains hydrophobic patches also called hydrophobic corridors that allow binding to nucleoporins, DNA-binding cofactors and various cytoplasmic proteins, as well as interaction with receptors.
Non-Canonical signaling
TGF-β non-canonical signaling pathway.
After ligand binding, several different branching signaling pathways can be activated in malignant cells, such as Notch signaling, MAP kinases, AKT/PKB pathway, GTP-binding proteins pathway, PTK pathway, NF-κB and Wnt/β-catenin pathway
TGF-beta and cell proliferation.
TGF-beta and cell proliferation.
The most critical effect of TGF-betaβ on target cells is suppression of proliferation. Its growth inhibitory function is based on the ability to suppress expression and function of c-Myc and cyclin-dependent kinases (CDKs) and to enhance expression of the CDK inhibitors p15 and p27.
TGF-beta and cell proliferation.
Mutations in TGF-beta and Cancer
TGF-beta acts as tumor promoter and is often over-expressed in many cancers.
Elevated plasma level of TGF-betaβ1 was observed in hepatocellular carcinoma, colon (HCC), prostate, lung and breast cancers and correlates with poor prognosis
TGF-beta and Cancer
Mutations in downstream TGF-beta signaling components cause variable attenuations, which have been detected in many human cancer development and progression
Tβ-beta-RI, Tβ-beta-RII, SMAD2 and SMAD4
-Inactivation of T-beta-RII leads to increased tumor spreading and metastasis in a variety of carcinomas, including colon, breast, pancreatic, intestinal or head and neck squamous cell carcinoma (HNSCC).
-Deregulated expression of Smurf1 and 2 was described. Several human carcinoma cell lines such as (colon HT-29,breast MDA-MB-231,gastric MKN-1) .
conclusion
TGF-beta signaling is complex and finely regulated fundamental pathway, which has an important role during human development and adult life.
It is broadly intertwined with other signaling pathways.
Moreover, it is involved in cancerogenesis of solid tumors as well as hematological malignancies. Paradoxically, TGF-beta is both a tumor suppressor and tumor promoter.