Entrainment (or resetting) of the clock occurs in response to new light–dark cycles. Although most Drosophila cells do not have true photoreceptors, light is sensed by intracellular flavoproteins, also called cryptochromes. In the presence of light, these proteins associate with the  Tim protein and cause its degradation, thereby resetting the clock. (Adapted from J.C. Dunlap, Science 311:184–186, 2006.) 1.2 1.0 0.8 0.6 0.4 0.2 cycle. Light is thought to affect the circadian clock indirectly: the activities of Kai proteins are influenced by changes in intracellular redox potential, which occur as a result of increased photosynthetic activity during the day.
Some signaling pathways that are especially important in animal development depend on proteolysis to control the activity and location of latent transcription regulatory proteins. Notch receptors are themselves such proteins, which are activated by cleavage when Delta on another cell binds to them; the cleaved cytosolic tail of Notch migrates into the nucleus, where it stimulates the transcription of Notch-responsive genes. In the Wnt/β-catenin signaling pathway, by contrast, the proteolysis of the latent transcription regulatory protein β-catenin is inhibited when a secreted Wnt protein binds to both a Frizzled and LRP receptor protein; as a result, β-catenin accumulates in the nucleus and activates the transcription of Wnt target genes.
Hedgehog signaling in flies works much like Wnt signaling. In the absence of a signal, a bifunctional, cytoplasmic transcription regulator, Ci, is proteolytically cleaved to form a transcriptional repressor that keeps Hedgehog target genes silenced. The binding of Hedgehog to its receptors (Patched and iHog) inhibits the proteolytic processing of Ci; as a result, the intact Ci protein accumulates in the nucleus and activates the transcription of Hedgehog-responsive genes. In Notch, Wnt, and Hedgehog signaling, the extracellular signal triggers a switch from transcriptional repression to transcriptional activation.
Signaling through the latent transcription regulator NFκB also depends on proteolysis. NFκB proteins are normally held in an inactive state by inhibitory IκB proteins in the cytoplasm. A variety of extracellular stimuli, including proinflammatory cytokines, trigger the phosphorylation and ubiquitylation of IκB, marking it for degradation; this enables the NFκB to translocate to the nucleus and activate