Transforming growth factor β (TGF-β) is expressed by all cells in the human body and plays an important role in normal development and homeostasis. There are three TGF-β forms (TGF-β1, 2, and 3), which are receptor ligands, have similar biological activity, and are important in processes such as regulating proliferation, migration, differentiation, and apoptosis. There are also three TGF-β receptors (TGFBR1, 2, and 3). Canonical TGF-β signaling occurs when one of the three ligands binds to TGFBR2, which then recruits and phosphorylates TGFBR1. TGFBR1 is the key component in passing extracellular stimulation to the downstream TGF-β signaling pathway. TGFBR1 can be phosphorylated at multiple sites, and it phosphorylates either downstream SMAD2/3 at the C-terminus, or kinases that activate noncanonical pathways. TGFBR1 is tightly controlled through ubiquitination, which regulates the amount of TGFBR1 protein and also mediates its activation of noncanonical signaling. TGFBR2 is the receptor that TGF-β binds directly, and thus it serves as a gatekeeper for the activation of downstream signaling. TGFBR2 is a constitutively active kinase independent of ligand binding, phosphorylating itself, TGFBR1, or other receptors. TGFBR3, also known as betaglycan, and is the most abundantly expressed TGFBR, TGF-β2 dictates disseminated tumor cell fate through TGFBR3 and p38α/β signaling.

References

1.Vander Ark A, et al. Cell Signal. 2018;52:112–120.