The TGF-beta superfamily contains molecules that encompass diverse functions during embryogenesis and adult tissue homeostasis. TGF-beta ligands are initially synthesized as precursor proteins that undergo proteolytic cleavage. The mature segments form dimers via disulfide links (except for GDF-3, -9, BMP-15, and Lefty), which serve as the active ligand. Although homodimers are considered the standard form, there are natural heterodimers with biological activity. TGF-beta ligand binds with a heteromeric receptor complex that consists of type I and type II serine/threonine kinase receptors. Upon phosphorylation by the constitutively-active type II receptor, type I receptor phosphorylates a receptor-activated smad (R-smad) protein initiating a signaling cascade that ultimately alters gene transcription. The type I – type II receptor combination, the activated smad pathway, and the cell-specific transcription factors may offer diversity in responses. Co-receptors and soluble or membrane-bound molecules regulate ligand access to the receptor complex, thereby fine-tuning TGF-beta signaling.
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