TGF-beta Superfamily

The transforming growth factor β (TGF-beta) superfamily, a group of multifunctional polypeptide, is the largest family of secreted growth factors composed of several subfamilies, including TGF-βs, bone morphogenetic proteins (BMPs), growth and differentiation factors (GDFs), activins, inhibins, and the glial cell-derived neurotrophic factors (GDNFs). TGF-β signaling is initiated by the binding of the ligand to heteromeric complexes comprised of type I and II transmembrane serine/threonine kinase receptors. Upon ligand binding, type II receptors transphosphorylate the type I receptors. The type I receptor kinase subsequently phosphorylates receptor-regulated Smads (R-Smads), which can then associate with the co-Smad, Smad4, and translocate to the nucleus and activate transcription of target genes. This is considered as the “Smad signaling pathway.” Additionally, the receptor complex can activate “non-Smad signaling pathways” through type II receptor– and type I receptor–interacting proteins. TGF-β superfamily members regulate various biological processes including cell proliferation, differentiation, migration, adhesion, apoptosis and extracellular matrix (ECM) production. TGF-β superfamily members also have been implicated in the pathogenesis of many diseases.