Key Concepts of Section 16.6

• Many signaling pathways involve ubiquitinylation and proteolysis of target proteins and so are irreversible or only slowly reversible. These target proteins can be either a transcription factor or an inhibitor of a transcription factor.

• Wnt controls numerous critical developmental events, such as brain development, limb patterning, and organogenesis. Hedgehog also functions as a morphogen during development. Activating mutations in both pathways can cause cancer.

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• Both Hedgehog and Wnt are secreted proteins that contain lipid anchors that reduce their signaling ranges. The fatty acid covalently attached to Wnt is essential for binding to its receptor.

• Wnt signals act through two cell-surface proteins, the receptor Frizzled and co-receptor LRP, and an intracellular complex containing β-catenin (see Figure 16-30). Binding of Wnt promotes the stability and nuclear localization of β-catenin, which either directly or indirectly promotes activation of the TCF transcription factor.

• Gradients of Wnt protein concentration are essential for many steps in development, including regeneration of a head and tail during planarian regeneration (see Figure 16-31).

• The Hedgehog signal also acts through two cell-surface proteins, Smoothened and Patched, and an intracellular complex containing the Cubitis interruptus (Ci) transcription factor (see Figure 16-33). An activating form of Ci is generated in the presence of Hedgehog; a repressing Ci fragment is generated in the absence of Hedgehog. Both Patched and Smoothened change their subcellular location in response to Hedgehog binding to Patched.

• Hh signaling in vertebrates requires primary cilia and intraflagellar transport proteins. Patched localizes to the ciliary membrane in the absence of Hh, and Smo moves to cilia when Hh is present (see Figure 16-34).

• The NF-κB transcription factor regulates many genes that permit cells to respond to infection and inflammation.

• In unstimulated cells, NF-κB is localized to the cytosol, bound to the inhibitor protein I-κBα. In response to many types of extracellular signals, phosphorylation-dependent ubiquitinylation and degradation of I-κBα in proteasomes releases active NF-κB, which translocates to the nucleus (see Figure 16-35a).

• Polyubiquitin chains linked to the activated IL-1 receptor form a scaffold that brings the TAK1 kinase near its substrate, the β subunit of the I-κB kinase, and thus allows signals to be transmitted from the receptor to downstream components of the NF-κB pathway (see Figure 16-35b).