TGFfamily

TGFfamily, also known as the transforming growth factor beta (TGF-β) superfamily, is a large group of secreted signaling proteins that regulate development, tissue homeostasis, and immune responses in animals. Members function as dimeric ligands that act through cell-surface receptors to influence a wide range of cellular processes.

Major subfamilies include TGF-βs (TGF-β1–β3), activins and inhibins, bone morphogenetic proteins (BMPs), growth and differentiation factors (GDFs), nodals, and lefty proteins. The ligands share a cystine-knot structural motif and are typically produced as latent precursors bound to latency-associated peptide, requiring proteolytic activation to signal.

Signaling occurs when a ligand binds a type II receptor, which recruits and phosphorylates a type I receptor. The activated receptor then phosphorylates receptor-regulated SMADs (R-SMADs). TGF-β, activin, and nodal subfamilies mainly activate SMAD2/3, whereas BMPs activate SMAD1/5/8. SMAD4 serves as the common-mediator SMAD that forms transcriptional complexes with R-SMADs. In addition to SMAD-dependent pathways, TGFfamily signaling engages SMAD-independent pathways such as MAPK and PI3K/AKT cascades.

Biological roles are diverse, including cell fate decisions during development, regulation of extracellular matrix and organogenesis, wound healing, and immune modulation. In adults, signaling maintains tissue homeostasis but can contribute to fibrosis or cancer progression depending on context. The family is evolutionarily conserved across metazoans, with a repertoire expanded by gene duplication and diversification in vertebrates.

Clinical relevance: Dysregulation or mutations affecting TGFfamily signaling are implicated in fibrotic diseases, vascular disorders, skeletal abnormalities, and various cancers. Therapeutic approaches target ligands, receptors, or SMAD signaling to modulate pathway activity.