In this section, we discuss an evolutionarily conserved family of receptor serine kinases (the TGF-β receptor family) and the conserved large family of signaling molecules (the TGF-β family) that bind to them. These receptors phosphorylate, and thus trigger the activation of, one conserved class of transcription factors (the Smads) that regulate several growth and differentiation pathways. In unstimulated cells, Smads are located in the cytosol, but when activated, they move into the nucleus to regulate transcription. The TGF-β pathway has widely diverse effects in different types of cells because different members of the TGF-β family activate different members of the TGF-β receptor family, which activate different members of the Smad class of transcription factors. In addition, we will see that the same activated Smad protein partners with different transcription factors, and thus activates different sets of genes, in different types of cells.

The transforming growth factor β (TGF-β) family includes a number of related extracellular signaling molecules that play widespread roles in regulating development in both invertebrates and vertebrates. The founding member of the TGF-β family, TGF-β1, was identified on the basis of its ability to induce a malignant phenotype in several cultured early-stage mammalian cancer cell lines (“transforming growth factor”); in this case, TGF-β1 promoted metastases, the spreading and invasion of primary tumors, as discussed in Chapter 24. However, the principal function of all three human TGF-β isoforms, TGF-β1, 2, and 3, in most normal (non-cancerous) mammalian cells is to prevent their proliferation by inducing the synthesis of proteins, including p15^INK4B, that inhibit the cyclin-dependent kinases (CDKs) that are essential for progression into the S phase of the cell cycle (see Figures 1-21 and 19-10).

TGF-β is produced by many cells in the body and inhibits the growth of both the secreting cell (autocrine signaling) and neighboring cells (paracrine signaling). Loss of TGF-β receptors, or of any of several intracellular signal-transducing proteins in the TGF-β pathway, releases cells from this growth inhibition and is seen frequently in the early development of human tumors. TGF-β proteins also promote expression of cell-adhesion molecules and extracellular-matrix molecules, which play important roles in tissue organization (see Chapter 20). A Drosophila homolog of TGF-β, called Dpp, participates in dorsal-ventral patterning in fly embryos. Other mammalian members of the TGF-β family, the activins and the inhibins, affect early development of the urogenital tract. Another member of this family, a bone morphogenetic protein (BMP), was initially identified by its ability to induce bone formation in cultured cells. Now called BMP7, it is used clinically to strengthen bone after severe fractures. Of the numerous BMP proteins subsequently recognized, many induce key steps in development, including formation of mesoderm and of the earliest blood-forming cells; some are important for maintaining the undifferentiated state in cultures of embryonic and adult stem cells (see Chapter 21). Most have nothing to do with bones.