Development - WNT signaling pathway. Part 2

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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