Having discussed the crucial role of tyrosine phosphorylation and dephosphorylation in the intracellular signaling pathways activated by many enzyme-coupled receptors, we now turn to a class of enzyme-coupled receptors that rely on serine and threonine phosphorylation. These receptor serine/threonine kinases activate an even more direct signaling pathway to the nucleus than does the JAK– STAT pathway. They directly phosphorylate latent transcription regulators called Smads, which then translocate into the nucleus to control gene transcription.
Signal Proteins of the TGFβ Superfamily Act Through Receptor Serine/Threonine Kinases and Smads
The transforming growth factor-β (TGFβ) superfamily consists of a large number (33 in humans) of structurally related, secreted, dimeric proteins. They act either as hormones or, more commonly, as local mediators to regulate a wide range of biological functions in all animals. During development, they regulate pattern formation and influence various cell behaviors, including proliferation, specification and differentiation, extracellular matrix production, and cell death. In adults, they are involved in tissue repair and in immune regulation, as well as in many other processes. The superfamily consists of the TGFβ/activin family and the larger bone morphogenetic protein (BMP) family.
All of these proteins act through enzyme-coupled receptors that are single-pass transmembrane proteins with a serine/threonine kinase domain on the cytosolic side of the plasma membrane. There are two classes of these receptor serine/threonine kinases—type I and type II—which are structurally similar homodimers. Each member of the TGFβ superfamily binds to a characteristic combination of type-I and type-II receptor dimers, bringing the kinase domains together so that the type-II receptor can phosphorylate and activate the type-I receptor, forming an active tetrameric receptor complex.
Once activated, the receptor complex uses a strategy for rapidly relaying the signal to the nucleus that is very similar to the JAK–STAT strategy used by cytokine receptors. The activated type-I receptor directly binds and phosphorylates a latent transcription regulator of the Smad family (named after the first two proteins identified, Sma in C. elegans and Mad in Drosophila). Activated TGFβ/ activin receptors phosphorylate Smad2 or Smad3, while activated BMP receptors phosphorylate Smad1, Smad5, or Smad8. Once one of these receptor-activated Smads (R-Smads) has been phosphorylated, it dissociates from the receptor and binds to Smad4 (called a co-Smad), which can form a complex with any of the five R-Smads. The Smad complex then translocates into the nucleus, where it associates with other transcription regulators and controls the transcription of specific target genes (Figure 15–57). Because the partner proteins in the nucleus vary depending on the cell type and state of the cell, the genes affected vary.
Activated TGFβ receptors and their bound ligand are endocytosed by two distinct routes, one leading to further activation and the other leading to inactivation. The activation route depends on clathrin-coated vesicles and leads to early endosomes (discussed in Chapter 13), where most of the Smad activation occurs. An anchoring protein called SARA (for Smad anchor for receptor activation) has an important role in this pathway; it is concentrated in early endosomes and binds to both activated TGFβ receptors and Smads, increasing the efficiency of receptor-mediated Smad phosphorylation. The inactivation route depends on caveolae (discussed in Chapter 13) and leads to receptor ubiquitylation and degradation in proteasomes.