Transforming growth factor-β (TGF-β) signaling plays a vital role in regulating cell growth, differentiation, and development in a wide array of biological systems.
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Members of the TGF-β family play a crucial role in tissue development, homeostasis and repair and negatively regulate the proliferation, differentiation and activation of all immune cells. TGF-β is therefore a potent immunosuppressor and disruption of the TGF-β signaling pathway is associated with autoimmune and inflammatory disorders, as well as cancer.
Signaling through TGF-β
The signaling pathway is initiated by ligand binding to the type II receptor (TGF-βRII), which leads to recruitment of the type I receptor (TGF-βRI) in a highly conserved region of the protein called the GS domain.
Activated TGF-βRI phosphorylates signal transducers SMAD2 and SMAD3, go on to form complexes with SMAD4. These complexes move into the nucleus, where they regulate DNA expression through interaction with ATF2 (Activating Transcription Factor-2) and SBE (SMAD Binding Element).
SMAD2-SMAD4 complexes specifically associate with DNA-binding proteins including Forkhead Activin Signal Transducer-2 (FAST2) to regulate transcriptional responses. Certain activated target genes trigger tumorigenesis, while others suppress it.
SMAD2 is later ubiquinated and targeted for degradation. Overexpression of SMAD7 prevents activated TGF-βRI from phosphorylating SMAD2 and SMAD3. SMAD6, which has a different structure to other SMAD proteins, forms a stable interaction with TGF-βRI.
It disrupts SMAD2 phosphorylation and therefore heteromerization with SMAD4, but it does not prevent SMAD3 activity. Structural elements in the kinase domain of the receptor and the MAD homology domain of SMAD determine the specificity of the receptor-SMAD association.
Prior to activation, factors such as SMAD Anchor for Receptor Activation (SARA), anchor receptor-regulated SMADs to the cell membrane to bring the SMADs within proximity of the receptor kinases. Non-SMAD signaling pathways are also activated by TGF-β, including activation of several MAP kinase kinase (MKKs) and MAPK/ERK Kinase (MEKs) pathways.
Regulation of TGF- β signalling
Due to the crucial role TGF-β signaling plays in the determination of cell fate, it is both positively and negatively regulated at multiple levels through targeting of both the receptors and the intracellular mediators.
Negative regulator of SMAD are c-Ski and c-SnON from the Ski family of proto-oncoproteins. These associate directly with SMAD2/SMAD3 and SMAD4 to inhibit TGF-β signaling and later regulate transcription by degrading releasing SMADs.
The Anaphase-Promoting Complex (APC) and cadherin-1 (Cdh1) are recruited to SnON by SMAD3, thereby providing an alternative way of targeting SnON for degradation. Aside from directly stimulating or repressing the expression of target genes, TGF-β also triggers various complex cellular responses, particularly growth arrest during late G1 phase of the cell cycle, alterations in differentiation and apoptosis. Other growth factors also regulate TGF-β signaling through Ras activation.
Disruption to TGF-β signalling
TGF-β proteins exert a multitude of effects, mediating homeostasis, angiogenesis, hormone secretion, tissue regeneration and the induction and modulation of bone. Disruption to the TGF-β signaling pathway has severe consequences and can result in a number of diseases including cancers of the blood, abnormal wound healing, neurodegenerative or developmental conditions and pulmonary hypertension.
When TGF-β signaling is impaired through genetic or epigenetic processes, tumorigenesis is promoted through immune system suppression alterations in epithelial tumor cell differentiation, referred to as Epithelial Mesenchymal Transdifferentiation (EMT). Furthermore, TGF-β signaling has been implicated in tumor inhibition processes such as genomic stability maintenance, telomerase activity suppression and inhibition of inappropriate angiogenesis.
A possible role of TGF-β in HIV1 gene regulation and pathogenesis has also been implicated, as increased levels among certain HIV1 patients promotes production of the virus, as well as disrupting the immune system.