Chapter 16: Signaling Pathways That Control Gene Expression

16.6 Signaling Pathways Controlled by Ubiquitinylation and Protein Degradation: Wnt, Hedgehog, and NF-κB

All the signaling pathways we have discussed so far are reversible and so can be turned off relatively quickly if the extracellular signal is removed. In this section, we discuss several irreversible or only slowly reversible pathways in which a critical component—either a transcription factor or an inhibitor of a transcription factor—is ubiquitinylated and then proteolytically cleaved. First we discuss signaling by Wnt and Hedgehog (Hh) proteins, two evolutionarily conserved families of signaling proteins that play key roles in many developmental pathways and often induce expression of genes required for a cell to acquire a new identify or fate. Although Wnt and Hedgehog signaling pathways use different sets of receptors and signaling proteins, they do share similarities, which is why we group them together:

In the resting state, key transcription factors in both pathways are ubiquitinylated and targeted for proteolytic cleavage, which renders them inactive.
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Activation of each pathway involves disassembly of large cytosolic protein complexes, inhibition of ubiquitinylation, and release of the active transcription factor.
Kinases, including glycogen synthase kinase 3 (GSK3), play key roles in both signaling pathways.

Next we examine the NF-κB pathway, a third signaling pathway controlled by ubiquitinylation. In this case, an inhibitor of a transcription factor, rather than a transcription factor itself, is degraded following ubiquitinylation. In the resting state, the transcription factor termed NF-κB is sequestered in the cytosol and bound to an inhibitor. Several stress-inducing conditions cause ubiquitinylation and immediate degradation of the inhibitor, allowing cells to respond immediately and vigorously by activating gene transcription. In learning how the NF-κB pathway is activated by one class of surface receptors, we also see a very different function of polyubiquitinylation: the formation of a scaffold to assemble a key signal transduction complex.