24.4:
Hedgehog Signaling Pathway
Hedgehog signaling is a conserved signaling pathway that regulates cell growth during embryonic development and tissue homeostasis, in invertebrates as well as vertebrates.
Unrestricted Hedgehog signaling can lead to several human developmental abnormalities and diseases including, cancers.
There are three key players in the Hedgehog signaling pathway.
The lipid-modified active Hedgehog ligand that acts as a local mediator, a transmembrane protein called Patched that acts as a receptor for the Hedgehog ligand and a transcription regulator called Cubitus Interruptus or Ci that acts as the primary effector molecule.
The Ci can exist in two different forms- an intact protein form, which acts as a transcriptional activator and a cleaved form called Ci75 which acts as a transcriptional repressor for various Hedgehog-responsive genes.
The intact Ci exists in association with a multiprotein complex bound to microtubules that consist of Fused kinase and Costal-2, a kinesin-like protein.
In the absence of Hedgehog ligand, the Patched protein continuously represses the activity of Smoothened protein – a transmembrane protein present on internal cell vesicles.
This elicits the processing of Ci by three kinases, PKA, GSK3, and CK1 which phosphorylate it and mark it for further processing in the proteasome, which results in the generation of Ci75.
Ci75 then translocates to the nucleus and assists in the transcriptional repression of the Hedgehog responsive genes in association with a co-repressor.
However, upon binding of the active Hedgehog ligand to the Patched protein and a co-receptor called iHog, the Smoothened protein is activated and transported to the cell membrane.
Then, smoothened recruits the components of the multiprotein complex to the membrane and interrupts the proteolysis of Cubitus Interruptus.
The intact Cubitus Interruptus then translocates to the nucleus and recruits another co-activator molecule to induce the expression of the Hedgehog responsive genes.
24.4:
Hedgehog Signaling Pathway
The Hedgehog gene (Hh) was first discovered due to its control of the growth of disorganized, hair-like bristles phenotype in Drosophila, much like hedgehog spines. Hh plays a crucial role in the development of organs and the maintenance of homeostasis in both invertebrates and vertebrates. However, while Drosophila has only one Hh protein, mammals have multiple functional Hedgehog proteins – Sonic (Shh), Desert (Dhh), and Indian Hedgehog (Ihh). All of these homologous proteins have adapted to perform specialized functions in different developmental processes in mammals. Additionally, unlike in invertebrate Hh signaling, mammalian Hedgehog signaling is also reliant upon a microtubule-based organelle called the primary cilium that is present on the cell surface of most vertebrate cells.
The Hedgehog Signaling Mechanism
The Hedgehog gene encodes for the Hedgehog precursor protein, which undergoes significant posttranslational modifications inside the endoplasmic reticulum. These lipid modifications of the Hedgehog protein play an essential role in the secretion of the active Hedgehog ligand from the signaling cell and its migration to the target cells. In the absence of active Hedgehog ligand, the Patched protein present on the target cell surface is the primary inhibitor of the downstream Hedgehog signaling. However, when the active Hedgehog ligand binds to the Patched protein, another transmembrane protein called Smoothened translocates to the cell surface. The Smoothened protein is then able to interrupt the activity of a multiprotein microtubule-associated complex in its degradation of Cubitus Interruptus. Cubitus Interruptus is the primary transcriptional activator in the Hh signaling pathway and subsequently translocates to the nucleus to turn on the expression of Hh target genes.
Functions and Associated Diseases
Hh signaling is crucial for organ development, and any disruptions to Hh during embryogenesis can lead to severe developmental abnormalities. Additionally, Hh signaling is essential for stem cell regeneration, which is responsible for the maintenance and regeneration of adult tissues. Abnormalities in the Hh signaling pathway can, therefore, lead to certain types of cancer, including pancreas, lung, prostate, breast, and brain tumors. Because of this, the Hh gene and signaling pathway is a valid therapeutic target for the pharmaceutical industry.
Suggested Reading
- Briscoe J. and Thérond P. P. The mechanisms of Hedgehog signalling and its roles in development and disease. Nature Reviews Molecular Cell Biology (2013) DOI:10.1038/nrm3598