Key Concepts of Section 16.1

• The transforming growth factor β (TGF-β) family includes a number of related extracellular signaling molecules that play widespread roles in regulating development.

• TGF-β dimers are stored in an inactive form on the cell surface or in the extracellular matrix; release of active dimers (e.g., by mechanical stretching of the prodomain or protease digestion) initiates TGF-β signaling.

• TGF-β receptors consist of three types (RI, RII, RIII). Binding of members of the TGF-β family to the RII receptor kinase allows RII to phosphorylate the cytosolic domain of the RI receptor and activate its intrinsic serine/threonine kinase activity. RI then phosphorylates an R-Smad, exposing a nuclear-localization signal (see Figure 16-3).

• After phosphorylated R-Smads bind a co-Smad, the resulting complex translocates into the nucleus, where it interacts with various transcription factors to induce expression of target genes (see Figure 16-3).

• The Smad3/Smad4 complex induces different genes in different cells by binding to regulatory DNA sequences at sites adjacent to those occupied by cell-specific master transcription factors (see Figure 16-4).

• TGF-β signaling generally inhibits cell proliferation. Loss of various components of this signaling pathway contributes to abnormal cell proliferation and malignancy.

• Oncoproteins (e.g., Ski and SnoN) and I-Smads (e.g., Smad7) act as negative regulators of TGF-β signaling by inhibiting transcription mediated by the Smad2/3/Smad4 complex (see Figure 16-5).