Smad signaling pathway. Smad pathway: TGF-β family members bind and signal through 2 types of serine/threonine kinase receptors, type I and type II, both of which are necessary for signal transduction. On ligand binding and receptor activation, the Smad proteins are activated through phosphorylation by type I receptors.^141,142  Three groups of Smads have been identified: receptor-activated Smads (R-Smads), common- partner Smads (Co-Smads), and inhibitory Smads (I-Smads). In general, TGF-β and activin signal via R-Smad2 and 3, whereas BMP signals are transduced through R-Smad1, 5, and 8. Phosphorylated R-Smads subsequently associate with the Co-Smad4, creating a complex that translocates to the nucleus where target gene transcription is modified. In contrast to R- and Co-Smads, the I-Smads, Smad6 and Smad7, function in a negative feedback loop to prevent activation of R-Smads.^143,–145  Divergence and convergence of the Smad signaling circuitry are depicted. Commonly used alternative names include: ALK2/Activin type I receptor, ALK3/BMP type IA receptor, ALK4/Activin type IB receptor, ALK5/TGF-β type I receptor, and ALK6/BMP type IB receptor. The shaded portion indicates the nucleus. P indicates phosphorylation.