The membrane proteoglycan betaglycan functions as a co-receptor that collects TGF-β for presentation to signaling receptors. TGF-β binds to two pairs of transmembrane serine/threonine protein kinases known as TGFBR1 (type I receptor) and TGFBR2 (type II receptor), to assemble the receptor complex. In this complex, TGFBR2 phosphorylates and activates the TGFBR1 kinase, which binds and phosphorylates (P) the transcription factors SMAD2 and SMAD3. On phosphorylation, these SMADs form trimeric complexes with SMAD4 and accumulate in the nucleus to transcriptionally activate target genes. Recognition of these loci by the SMAD complex frequently requires molecular interaction with lineage-determining transcription factors (LDTFs) or signal-driven transcription factors (SDTFs). The signaling cycle ends with SMAD dephosphorylation and dissociation from DNA for another round of signaling, or with SMAD polyubiquitination and degradation. Each step in the pathway is controlled by different classes of regulators, the most prominent of which are listed (with examples).
