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Diagram: notch signaling pathway in
Homo sapiens
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Diagram: Notch signaling in
Drosophila
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Netpath - A curated resource of signal transduction pathways in humans
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MeSH
Notch+Receptors
The Notch signaling pathway is an evolutionarily conserved, intercellular signaling mechanism essential for proper embryonic
development in all metazoan organisms in the Animal kingdom. The Notch proteins (Notch1-Notch4 in vertebrates) are single-pass
receptors that are activated by the Delta (or Delta-like) and Jagged/Serrate families of membrane-bound ligands. They are
transported to the plasma membrane as cleaved, but otherwise intact polypeptides. Interaction with ligand leads to two additional
proteolytic cleavages that liberate the Notch intracellular domain (NICD) from the plasma membrane. The NICD translocates to the
nucleus, where it forms a complex with the DNA binding protein CSL, displacing a histone deacetylase (HDAc)-co-repressor (CoR)
complex from CSL. Components of an activation complex, such as MAML1 and histone acetyltransferases (HATs), are recruited to
the NICD-CSL complex, leading to the transcriptional activation of Notch target genes.
Hedgehog signaling pathway
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In a growing embryo, cells develop differently in the head or tail end of the embryo, the left or right, and other positions. They also form segments which develop
into different body parts. The hedgehog signaling pathway gives cells information that they need to make the embryo develop properly. Different parts of the
embryo have different concentrations of hedgehog signaling proteins. The pathway also has roles in the adult. When the pathway malfunctions, it can result in
diseases like basal cell carcinoma.
[1]
The hedgehog signaling pathway is one of the key regulators of animal development conserved from flies to humans (meaning it was present in the common ancestor
of both). The pathway takes its name from its polypeptide ligand, an intercellular signaling molecule called Hedgehog (
Hh) found in fruit flies of the genus
Drosophila. Hh is one of Drosophila's segment polarity gene products, involved in establishing the basis of the fly body plan. The molecule remains important during
later stages of embryogenesis and metamorphosis.
Mammals have three Hedgehog homologues, of which Sonic hedgehog is the best studied. The pathway is equally important during vertebrate embryonic
development. In knockout mice lacking components of the pathway, the brain, skeleton, musculature, gastrointestinal tract and lungs fail to develop correctly. Recent
studies point to the role of hedgehog signaling in regulating adult stem cells involved in maintenance and regeneration of adult tissues. The pathway has also been
implicated in the development of some cancers. Drugs that specifically target hedgehog signaling to fight this disease are being actively developed by a number of
pharmaceutical companies.
[edit] Discovery
Figure 1. Normal and Hedgehog mutant larvae.
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In the 1970s, a fundamental problem in developmental biology was to understand how a relatively simple egg can give rise to a complex segmented body plan. In the
late 1970s Christiane Nüsslein-Volhard and Eric Wieschaus isolated mutations in genes that control development of the segmented anterior-posterior body axis of the
fly;
[2]
their "saturation mutagenesis" technique resulted in the discovery of a group of genes involved in the development of body segmentation. In 1995, they shared
the Nobel Prize with Edward B. Lewis for their work studying genetic mutations in Drosophila embryogenesis.
[3]
The Drosophila hedgehog (hh) gene was identified as one of several genes important for creating the differences between the anterior and posterior parts of
individual body segments. The fly hh gene was independently cloned in 1992 by the labs of Jym Mohler, Philip Beachy, and Thomas B. Kornberg. Some hedgehog
mutants result in abnormally-shaped embryos that are unusually short and stubby compared to wild type embryos. The function of the hedgehog segment polarity
gene has been studied in terms of its influence on the normally polarized distribution of larval cuticular denticles as well as features on adult appendages such as legs
and antennae.
[4]
Rather than the normal pattern of denticles, hedgehog mutant larvae tend to have "solid lawns" of denticles (Figure 1). The appearance of the stubby
and "hairy" larvae inspired the name 'hedgehog' (see: Hedgehog, the animal).
[edit] Fruit fly
Figure 2. Production of the CiR transcriptional repressor when Hh is not
bound to Patched. In the diagram, "P" represents phosphate.
Figure 3. When Hh is bound to Patched (PTCH), Ci protein is able to act as a transcription factor in the nucleus.
[edit] Mechanism
Insect cells express a full size zinc-finger transcription factor Cubitus interruptus (Ci), which forms a complex with the kinesin- like protein Costal-2 (Cos2) and is
localized in the cytoplasm bound to cellular microtubules (Figure 2). The complex targets the 155 kb full length Ci protein for proteosome- dependent cleavage,
which generates a 75 kb fragment (CiR). CiR builds up in the cell and diffuses into the nucleus, where it acts as a co-repressor for Hh target genes.
[5]
The steps
leading to Ci protein proteolysis include phosphorylation of Ci protein by several protein kinases; PKA, GSK3β and CK1 (Figure 2).
[6]
The
Drosophila protein Slimb
is part of an SCF complex that targets proteins for ubiquitylation. Slimb binds to phosphorylated Ci protein.
In the absence of Hh (Figure 3), a cell-surface transmembrane protein called Patched (PTCH) acts to prevent high expression and activity of a 7 membrane spanning
receptor
[7]
called Smoothened (SMO). Patched has sequence similarity to known membrane transport proteins. When extracellular Hh is present (Figure 3), it binds
to and inhibits Patched, allowing Smoothened to accumulate and inhibit the proteolytic cleavage of the Ci protein. This process most likely involves the direct
interaction of Smoothened and Costal-2 and may involve sequestration of the Ci protein-containing complex to a microdomain where the steps leading to Ci protein