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Wnt and Shh are two highly studied developmental cell signals / ligands. They can act separately
as well as together to regulate embryonic development and adult cell biology – e.g. stem cells,
cancer.
Wnts
Small secreted proteins (~40 kDa) that act as local mediators & morphogens
Ancient, with shared amino acid sequence
Made by all animals (Humans have 19 Wnts. Distinct functions but can overlap)
Glycosylated & lipid modified (FA chain on N-terminus binding to cell surfaces)
Many molecules interact with Wnts
Involved in most cell signalling events during development and adult life
Clinical importance – e.g. inherited diseases in embryonic development
Involved over many different timescales
PCP pathway is important in Drosophila development. The pathway can be disrupted then the
phenotype can be monitored for changes.
e.g. In humans cilia will not develop properly in the ear, resulting in deafness.
2. Ca2+
Wnt / Ca2+ regulated enzymes / change in gene transcription
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Molecular Cell Biology II Signalling During Vertebrate Development I - Wnts
The degradation complex binds -catenin and keeps it out of the nucleus, as well as promoting
its degradation. The complex consists of…
Casein Kinase 1 (CK1) – A Ser / Thr kinase
Glycogen Synthase Kinase 3 (GSK3) – A Ser / Thr kinase
Axin – Scaffold protein*
APC – Scaffold protein*, involved in colon tumors
*Scaffold proteins hold complexes together
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Molecular Cell Biology II Signalling During Vertebrate Development I - Wnts
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Molecular Cell Biology II Signalling During Vertebrate Development I - Wnts
When studying development with regards to Wnts, it is important to take a few facts into
consideration. There are many possible points of regulation between ligand production and target
response, which increases complexity. The response of a cell to a signal is context dependent,
and down to a complex range of parameters. There are often differences between species, and
in vitro studies do not always replicate what is going on in vivo.
These two modifications will result in the Wnt having a larger mass than expected3
The Wnts can then be loaded onto a lipoprotein in specific endo / exocytic vesicles. Wnts can
interact well with other proteins.
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Molecular Cell Biology II Signalling During Vertebrate Development I - Wnts
A morphogen is a signal that forms gradients and has concentration dependent effects on
responsive cells. The result of this signal is the choice of cell fate and differentiation.
Positional value is interpreted by cells, which allows them to form a pattern.
The simplest way to control the amount of Wnt that reaches the target cell is to make more of less
of the molecule.
Another method is to produce extracellular molecules that bind to the Wnt and prevent it from
binding to the target cell.
Conversely, an extracellular molecule can bind to the Wnt, stabilise it and then present it to the
target cell with greater affinity.
A point of regulation – Dkk proteins bind LRP and link it to Kremens, triggering internalisation
Some proteins can activate / block Wnts depending on context (receptors, receptor state, co-
receptors, downstream enzymes, genes expressed, cell cycle etc.)
There are many points of possible Wnt signalling regulation
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Molecular Cell Biology II Signalling During Vertebrate Development I - Wnts
Also involved in hair follicle tumors and baldness, Wnt and -catenin are heavily involved in
follicles for hair formation.
Many pharma companies are looking for molecules that are Wnt modulators
These are obviously toxic, so aim is to develop non-toxic inhibitors of Wnts for cancer treatment
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