When active dimerized TGFβ is released from the large latent complex through one of the regulatory mechanisms mentioned above, it binds to a dimer of a constitutively active serine/threonine kinase receptor known as TGFβ receptor Type II or TβRII. This entity recruits a second receptor dimer, TβRI, which is phosphorylated by TβRII (also known as ALK5; see legend to Figure 1 and Table 1). The resulting heterotetramer, stabilized by the ligand, is shown in Figure 1. Phosphorylated and activated TβRI phosphorylates Smads 2 and 3, which combine with Smad 4 to form a heterotrimer that enters the nucleus and interacts with co-repressor or co-activation proteins in the transcription complex of specific genes to alter the pattern of gene expression of the cell. Table 1 lists some of the individual proteins that form the signaling complexes that participate in signaling by members of the TGFβ family of growth factors.
Fig2. TGFβ signaling. TGFβ, like other members of its family, interacts sequentially with two different types of receptor, TGFβRI and TGFβRII. The type 1 receptor, ALK-5, is one of seven ALK (Activin receptor-Like Kinase) receptor proteins that serve as the Type I receptors for other members of the TGFβ family of growth factors (see Table 1). Dimerized active TGFβ binds to a dimer of TGFβRII (yellow), which recruits a dimer of TGFβRI (blue); the heterotetrameric complex is stabilized by the bound ligand. The constitutively active serine/threonine kinase of the Type II receptor phosphorylates the Type I receptor, which phosphorylates Smads 2 and 3, two of the regulatory Smads. These are joined by a co-regulating Smad, Smad 4, in a heterotrimer which enters the nucleus and interacts with transcriptional co-activators and co-repressors to modulate, along with other transcription factors, the rate of gene transcription.
Table1. TGFβ Family: Typical Signaling Components a
There are eight Smad proteins in vertebrates. Smads 1,2,3, 5, and 8 are phosphorylated and regulated by the activated receptors for members of the TGFβ family as described above and are referred to as R-Smads. Smad 4 participates in translocation into the nucleus for binding to a transcriptional complex and is referred to as a co-Smad. Smads 6 and 7 compete with Smad 4 in this function and are therefore known as I (inhibitory) Smads.
TGFβ is also capable of stimulating non-Smad signaling pathways. For example, TβRI can phosphorylate tyrosines of ShcA leading to the recruitment of GRB2/ SOS, Ras activation, and activation of the MAP kinase pathway. There is also considerable crosstalk between downstream mediators in one signaling pathway with those in another in response to TGFβ, so it is important to recognize that while the Smad pathway is central to the actions of TGFβ and other members of this family, it does not operate in isolation from other pathways.
