In the absence of Wnt signaling, Wnt-responsive genes are kept silent by an inhibitory complex of transcription regulatory proteins. The complex includes proteins of the LEF1/TCF family bound to a co-repressor protein of the Groucho family (see Figure 15–60A). In response to a Wnt signal, β-catenin enters the nucleus and binds to the LEF1/TCF proteins, displacing Groucho. The β-catenin now functions as a coactivator, inducing the transcription of the Wnt target genes (see Figure 15–60B). Thus, as in the case of Notch signaling, Wnt/β-catenin signaling triggers a switch from transcriptional repression to transcriptional activation.
Among the genes activated by β-catenin is Myc, which encodes a protein (Myc) that is an important regulator of cell growth and proliferation (discussed in Chapter 17). Mutations of the Apc gene occur in 80% of human colon cancers (discussed in Chapter 20). These mutations inhibit the protein’s ability to bind β-catenin, so that β-catenin accumulates in the nucleus and stimulates the transcription of c-Myc and other Wnt target genes, even in the absence of Wnt signaling. The resulting uncontrolled cell growth and proliferation promote the development of cancer.
Various secreted inhibitory proteins regulate Wnt signaling in development. Some bind to the LRP receptors and promote their down-regulation, whereas others compete with Frizzled receptors for secreted Wnts. In Drosophila at least, Wnts activate negative feedback loops, in which Wnt target genes encode proteins that help shut the response off; some of these proteins inhibit Dishevelled, and others are secreted inhibitors.
Hedgehog Proteins Bind to Patched, Relieving Its Inhibition of Smoothened
Hedgehog proteins and Wnt proteins act in similar ways. Both are secreted signal molecules, which act as local mediators and morphogens in many developing invertebrate and vertebrate tissues. Both proteins are modified by covalently attached lipids, depend on secreted or cell-surface-bound heparan sulfate proteoglycans (discussed in Chapter 19) for their action, and activate latent transcription regulators by inhibiting their degradation. They both trigger a switch from transcriptional repression to transcriptional activation, and excessive signaling along either pathway in adult cells can lead to cancer. They even use some of the same intracellular signaling proteins and sometimes collaborate to mediate a response.
The Hedgehog proteins were discovered in Drosophila, where this protein family has only one member. Mutation of the Hedgehog gene produces a larva covered with spiky processes (denticles), like a hedgehog. At least three genes encode Hedgehog proteins in vertebrates—Sonic, Desert, and Indian hedgehog. The active forms of all Hedgehog proteins are covalently coupled to cholesterol, as well as to a fatty acid chain. The cholesterol is added during an unusual processing step, in which a precursor protein cleaves itself to produce a smaller, cholesterol-containing signal protein. Most of what we know about the Hedgehog signaling pathway came initially from genetic studies in flies, and it is the fly pathway that we summarize here.