Hedgehog signaling pathway

The Hedgehog signaling pathway is a signal transduction pathway that can react through the cells to external signals. The signal path is named after its ligand Hedgehog ( Hh ), a signaling protein that plays a major role in the embryonic development of animals as a local morphogen and occurred very early in the evolutionary history. A malfunction of this pathway leads to massive malformations during embryonic development and may cause cancer in adults. In mammals, are currently three hedgehog proteins known ( sonic hedgehog, Indian hedgehog and desert hedgehog ).

Operation

The Hedgehog signaling pathway is based on the proteolysis and is activated when the hedgehog protein binds to the receptor, Patched ( Ptch ). Characterized passes another membrane-bound protein, smoothened (SMO), a signal further into the cell, which prevents the degradation of the regulatory protein C ( cubitus interruptus ). This is without the influence of hedgehog protein in a larger complex - consisting of the protein Costal, the serine-threonine kinase fused ( fu ) and the inhibitor of Fused - mined. Now, if Hedgehog is active and a signal passes, the protein C may not be degraded, diffuses into the nucleus and regulates gene expression there.

Occurrence

Hedgehog -like genes and two homologs of patched have been found in the nematode C. elegans, and has been demonstrated that these genes play an important role in the development of C. elegans, such as in other animals.

In insects, the Hedgehog signaling pathway controls the correct performance of segmentation and wing formation. In vertebrates, however, it induces the left-right symmetry and is responsible for the correct formation of limb rudiments.

Discovery

The gene that encodes for the Drosophila melanogaster Hedgehog for, was among the first to be important for the development described genes. It was first described by researchers Christiane Nüsslein- Volhard and Eric F. Wieschaus ( both of which were in 1995 a Nobel Prize " for their basic understanding of the genetic control of early embryonic development " ), where they discovered through a genetic screen different mutations that embryonic development influenced by Drosophila. The name Hedgehog (English for hedgehogs ') stirred because also of the " hedgehog -like " appearance of fly larvae forth, carrying a mutation in the gene for hedgehog.

Inhibition

Inhibition of the hedgehog signaling pathway is a new therapeutic principle in the treatment of certain cancers such as basal cell carcinoma or medulloblastoma. In basal cell carcinomas and other tumors solidern there is often an abnormal activation of the Hedgehog signaling pathway, which in adults is normally inactive. The first representative of the new class of drugs used therapeutically the Hedgehog pathway inhibitors is Vismodegib ("first -in-class " ), experimental drugs in clinical trials, for example, Sonidegib and Saridegib. They selectively inhibit the transmembrane receptor Smoothened ( SMO).