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Do you know what is common between the 2 pictures shown
above? They are both called ‘Sonic Hedgehog’! That’s true – in biochemistry,
there is a signaling pathway known as the ‘Hedgehog Pathway’, and the proteins
involved have funny names like ‘Sonic hedgehog’, ‘Smoothened’ and ‘Patched’.
The April issue of Nature Chemical Biology has a really great perspective
article on this pathway and the drug development involving this cell signaling
circuit. [1] Indeed, Smoothened is an oncoprotein , which is coded by an oncogene.
Oncogenes are obviously important because they are the ones which are
overexpressed in pathological situations and ultimately lead to many type of
cancer. The Hedgehog pathway is an very important signaling pathway, as it is
actively involved in development. Of course, it is not at all an issue when you
are developing, e.g. a fetus, but it is a big problem when you are mature. If
these genes are overexpressed, it is a sort of ‘over-reaction’ and the ultimate
result is malignancy. It has been shown that the abnormal signaling of Hedgehog
pathway can lead to basal cell carcinoma and also some childhood tumors. This
article has a bit of molecular biology and chemistry, and should be really
useful for biochemistry and molecular biology students.
A diagram explaining the Hedgehog Signalling Pathway. Taken from [2].
I would also like to provide a brief discussion about the
Hedgehog pathway here. At the start, the
protein ‘Patched’ inhibit the activity of ‘Smoothened’, which is a
7-transmembrane spanning, GPCR like protein. After the Hedgehog protein is
cleaved and covalently modified by the addition of a palmitoyl and a
cholesterol group ( both are fatty groups), that becomes hydrophobic and so it
can associate with the membrane and its diffusion ability will be limited as a result. This is indeed
important because it has be previously shown that a reasonable amount of
Hedgehog protein has to be present to effect downstream signaling, and so the
limited diffusion will help to establish
a concentration of the Hedgehog protein. Now, before we understand what the Hedgehog
protein is up to, let us divert ourselves for one further detail. In the cell
there exists a Hedgehog signaling complex (HSC), which is a series of protein
that is associated with the microtubule in the cell. Among those proteins is a
transcription factor called Ci, and when Ci is cleaved, it moves into the
nucleus and lead to a reduced transcription of relevant genes. However, when Hedgehog protein is present, it
binds to Patched, which no longer inhibits the Smoothened Protein. To state it
another way, the Hedgehog protein ‘releases’ the Smoothened protein indirectly.
Smoothened is then phosphorylated by Protein Kinase A and Casein Kinase 1.
Phosphorylations also occur for the other proteins in HSC and they associate
with the phosphorylated Smoothened. Eventually, the HSC complex is no longer
associated with the microtubule, and Ci is not cleaved. Therefore, the intact Ci cannot repress transcription as
a result. That is why Smoothened is an oncoprotein – because it leads to an
intact Ci, which is not able to put a brake on the transcription. The wheel
goes on and then ‘abnormal’ proteins are over-produced as a result. Given that
‘Smoothened’ and ‘Patched’ are nemesis, it won’t be too wrong to say ‘Smooth
the Patchy Hedgehog’!
If you are interested, you can explore more about this in any biochemistry textbooks - a reasonably great understanding has been developed about this fascinating pathway.
by Ed Law
28/4/2015
Reference:
1. Regulation of the oncoprotein Smoothened by small molecules
Hayley J Sharpe, Weiru Wang, Rami N Hannoush & Frederic J de Sauvage
Nature Chemical Biology, 2015, 11, 246-255.
doi:10.1038/nchembio.1776
2. http://www.novusbio.com/hedgehogpathway.html
