WNT signaling pathway. Part 2
Wingless-type MMTV integration site family (WNT) signaling
components are a family of secreted glycoproteins, and 19 human Wnt
genes have been identified to date (see Wnt homepage at
http://www.stanford.edu/~rnusse/wntwindow.html). WNT regulates a
variety of biological processes including embryonic development, body
patterning, tissue morphogenesis, epithelial-to-mesenchymal transition
(EMT) and tumorigenesis. WNT ligands bind to the 'frizzled'
seven-transmembrane receptors (Frizzled) and the Low density
lipoprotein receptor-related protein 5 and 6 (LRP-5 and LRP-6) in
the canonical WNT pathway [1].
In the canonical WNT pathway, WNT binding to Frizzled and
LRP receptors induces phosphorylation of Dishevelled proteins (Dsh)
by Casein kinases, which in turn causes inhibition of Glycogen
synthase kinase 3 beta (GSK-3 beta). In the absence of WNT
signaling, active GSK-3 beta phosphorylates Beta-catenin,
resulting in its ubiquitination and proteasomal degradation. In the
presence of WNT signal, GSK-3 beta is inhibited and the
unphosphorylated Beta-catenin is stable in the cytosol and
travels into the nucleus where it acts as a co-activator with Tcf (Lef)
transcription factors [1]. Beta-catenin
- Tcf (Lef) transcriptional activity regulates expression of a
number of target genes such as Cyclin D1, c-Jun, c-Myc,
E-cadherin, and matrix metalloproteinases (MMP), including MMP-7
and MMP-26 [2]
WNT/Beta-catenin pathway is linked to EMT process.
Preliminary this pathway is studied during cancer progression [3],
[4]. The extent of WNT pathway
participation in EMT process during embryogenesis or wound healing is
not elucidated, but it is known to take place during embryonic cell
differentiation [5], [6],
[7], [8]. This
participation can be explained by Beta-catenin and Snail homolog
1 (SNAIL1) stabilization. WNT via binding to Frizzled
[9] induces Glycogen synthase kinase 3 beta (GSK3
beta) inhibition. This prevents GSK3 beta mediated inhibition
of SNAIL1 and Beta-catenin signaling. SNAIL1
decreases Cadherin 1 type 1 E-cadherin (E-cadherin) [10],
[11], [12]. Beta-catenin
translocates to nucleus, activates transcription factor Lymphoid
enhancer-binding factor 1 (Lef-1) [9],
which is known to activate expression of Snail homolog 2 (SLUG)
and also decrease E-cadherin [11], [13],
[14]. WNT1 and WNT6 are shown
to induce EMT [5], [6],
[10], [15]. WNT4
and WNT9b induce mesenchymal-to-epithelial transition (MET)
during nephrogenesis via canonical pathway of Beta-catenin
stabilization [16], [17].
But canonical pathway is not sufficient for full tubulogenesis. And
additionally WNT4 induces non-canonical pathways for this process
[18].
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