Transforming growth factor beta (TGF-β) is a cytokine that participates in both physiological and pathological processes. During tumor progression, TGF-β signaling regulates immune/inflammatory response and tumor microenvironment. The TGF-β superfamily consists of at least 40 structurally and functionally related cytokines. TGF-β family proteins are classified into several subtypes, including TGF-βs, activins/inhibins, and bone morphogenetic proteins (BMPs)/growth differentiation factors according to structural characteristics. TGF-β signals through TGF-β receptors (TGF-βRs, TβRs) I and II to activate downstream signaling pathways. The TGF-βRs are single-pass transmembrane proteins with serine/threonine kinase activity. In the absence of ligand, TGF-βRI and TGF-βRII exist as monomers, homodimers, or heterodimers on the cell surface. Ligand binding promotes formation of a tetrameric complex between TGF-βRII dimers and two TGF-βRIs. TGF-βRIs and TGF-βRIIs have N-terminal extracellular ligand binding domains, transmembrane segments, and C-terminal cytosolicserine/threonine kinase domains. TGF-β binds specifically to the constitutively active TGF-βRII, which activates TGF-βRI by phosphorylating the glycine/serine-rich domain. Activated TGF-βRI then phosphorylates downstream effectors to induce signal transduction. TGF-βR activity is regulated by beta glycan, a type III TGF-βR, and endoglin.
Canonical TGF-β signaling is dependent upon Smad family proteins. Active TGF-βI at the cell surface phosphorylates receptor-activated Smads (R-Smads). There are two sub-classes of R-Smads in which Smad2 and Smad3 mediate the TGF-β/activin pathway. Smad4 acts as a co-factor that binds to activated R-Smads to form a complex that translocates to the nucleus and regulates transcription. TβRs can also activate non-Smad-dependent signaling pathways, including the mitogen-activated protein kinase (MAPK) pathway mediated by p38, c-Jun amino terminal kinase (JNK), extracellular signal-regulated kinases (ERK), nuclear factor-κB (NF-κB), Rho, and phosphatidylinositol 3-kinase (PI3K)-Akt. TGF-β pathway is a very complex signaling network, and its role in cellular homeostasis varies with different genetic profiles of cancer cells. On the one hand, TGF-β signaling can induce cell differentiation and act as a tumor suppressor in non-malignant tumor, on the other hand, it is also capable of promoting angiogenesis and EMT in cancer cells. Once signal transduction is initiated, TGF-β is involved in cell differentiation and can also act as a tumor suppressor in cell cycle control. Furthermore, TGF-β induces p53-independent expression of p21 and inhibits oncogene expression, while TGF-β receptors also cross-talk with oncogenic signaling pathways. TGF-β pathway has dual anti- and pro-tumoral roles at the cancer cell level, depending on tumor stage and genetic alteration background, with mechanistic differences between cancer models.
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