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Anita Hall - Wnts

Anita Hall - Wnts

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Published by Miles Nsg

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Published by: Miles Nsg on Feb 07, 2011
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Molecular Cell Biology II Signalling During Vertebrate Development I - Wnts[Page 1]Wnt and Shh are two highly studied developmental cell signals / ligands. They can act separately as well astogether to regulate embryonic development and adult cell biology ² e.g. stem cells, cancer.Wnts
 
Small secreted proteins (~40 kDa) that act as local mediators & morphogens
 
A
ncient, with shared amino acid sequence
 
Made by all animals (Humans have 19 Wnts. Distinct functions but can overlap)
 
G
lycosylated & lipid modified (F
A
chain on N-terminus
o
binding to cell surfaces)
 
Many molecules interact with WntsInvolved in most cell signalling events during development and adult lifeClinical importance ² e.g. inherited diseases in embryonic developmentInvolved over many different timescales3 major Wnt signalling pathways:1. Planar Cell Polarity (PCP)
 
Wnt / Jun Kinase (JNK) / cytoskeleton regulation / polarity
 
Important for changing cell shape
 
Important for cell migration ² involved in cancer metastasisPCP pathway is important in Drosophila development. The pathway can be disrupted then the phenotype canbe monitored for changes.e.g. In humans cilia will not develop properly in the ear, resulting in deafness.2. Ca
2+
 
Wnt / Ca
2+
regulated enzymes / change in gene transcription3. Canonical (Wnt /
F
-catenin)
A
ll 3 major Wnt signalling pathways start in the same way:1. Wnt binds to a Frizzled cell surface receptor 
 
7
-pass,
G
PCR (
G
-Protein Coupled Receptor) like
 
Humans have
7
frizzleds2. Frizzled can then bind Dishevelled (scaffold protein)
 
Dishevelled is required for all 3 pathwaysCanonical Pathway (Wnt /
F
-catenin):
 
Molecular Cell Biology II Signalling During Vertebrate Development I - Wnts[Page 2]Regulates proteolysis of 
F
-catenin which functions in gene regulation as well as cell-cell adhesionWnt binds to Frizzled protein and a co-receptor ² LDL-LRP
 
(low-density lipoprotein receptor-related protein)The degradation complex binds
F
-catenin and keeps it out of the nucleus, as well as promoting itsdegradation. The complex consists of«
 
Casein Kinase 1 (CK1) ²
A
Ser / Thr kinase
 
G
lycogen Synthase Kinase 3 (
G
SK3) ²
A
Ser / Thr kinase
 
A
xin ² Scaffold protein
*
 
 
A
PC ² Scaffold protein
*
, involved in colon tumors
*Scaffold proteins hold complexes together 
Canonical Signalling Pathway:In absence of Wnt signal1.
F
-catenin binds degradation complex2. CK1 phosphorylates
F
-catenin (priming)3.
G
SK3 phosphorylates
F
-catenin4. The double phosphorylated
F
-catenin is now targeted for degradation
 
Via ubiquitination and the proteasome5.
F
-catenin cannot enter the nucleus6. Wnt responsive genes are kept inactive by the
G
roucho co-repressor protein
 
G
roucho is bound to the gene regulatory protein LEF1/TCFWith Wnt Signal1. Wnt binds to Frizzled and LRP, bringing the two receptors together 2. This recruits the degradation complex to the plasma membrane3.
G
SK3 and CK1 phosphorylate the cytosolic tail of LRP4.
A
xin binds to the phosphorylated LRP and is inactivated / degraded5. Loss of axin from degradation complex inactivates it
 
F
-catenin is no longer phosphorylated or ubiquitinated
 
F
-catenin will not be degraded, so it will accumulate and enter the nucleus6. Within the nucleus,
F
-catenin binds to LEF1/TCF, displaces
G
roucho and acts as a co-activator to stimulatetranscription on Wnt target genes. It can alter local chromatin structure and recruit other transcription factors.
 
Molecular Cell Biology II Signalling During Vertebrate Development I - Wnts[Page 3]How does
F
-catenin enter the nucleus?
 
Does not enter via a nuclear localisation signal or importin
 
It can bind to a nuclear pore
 
Has an export signal and can ¶piggy back· out of the nucleus on axinWnt /
F
-catenin target genes: The downstream effectc-Myc is an example of a gene that is activated by
F
-cateninIt encodes a protein that is a powerful stimulator of cell growth and proliferation

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