Development - WNT signaling pathway. Part 2

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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].



References

  1. Clevers H
    Wnt/beta-catenin signaling in development and disease. Cell 2006 Nov 3;127(3):469-80
  2. Willert K, Jones KA
    Wnt signaling: is the party in the nucleus? Genes & development 2006 Jun 1;20(11):1394-404
  3. Yook JI, Li XY, Ota I, Hu C, Kim HS, Kim NH, Cha SY, Ryu JK, Choi YJ, Kim J, Fearon ER, Weiss SJ
    A Wnt-Axin2-GSK3beta cascade regulates Snail1 activity in breast cancer cells. Nature cell biology 2006 Dec;8(12):1398-406
  4. Guo Y, Zi X, Koontz Z, Kim A, Xie J, Gorlick R, Holcombe RF, Hoang BH
    Blocking Wnt/LRP5 signaling by a soluble receptor modulates the epithelial to mesenchymal transition and suppresses met and metalloproteinases in osteosarcoma Saos-2 cells. Journal of orthopaedic research : official publication of the Orthopaedic Research Society 2007 Jul;25(7):964-71
  5. Shimamura K, Hirano S, McMahon AP, Takeichi M
    Wnt-1-dependent regulation of local E-cadherin and alpha N-catenin expression in the embryonic mouse brain. Development (Cambridge, England) 1994 Aug;120(8):2225-34
  6. Schubert FR, Mootoosamy RC, Walters EH, Graham A, Tumiotto L, Münsterberg AE, Lumsden A, Dietrich S
    Wnt6 marks sites of epithelial transformations in the chick embryo. Mechanisms of development 2002 Jun;114(1-2):143-8
  7. Ullmann U, Gilles C, De Rycke M, Van de Velde H, Sermon K, Liebaers I
    GSK-3-specific inhibitor-supplemented hESC medium prevents the epithelial-mesenchymal transition process and the up-regulation of matrix metalloproteinases in hESCs cultured in feeder-free conditions. Molecular human reproduction 2008 Mar;14(3):169-79
  8. ten Berge D, Koole W, Fuerer C, Fish M, Eroglu E, Nusse R
    Wnt signaling mediates self-organization and axis formation in embryoid bodies. Cell stem cell 2008 Nov 6;3(5):508-18
  9. Couffinhal T, Dufourcq P, Duplàa C
    Beta-catenin nuclear activation: common pathway between Wnt and growth factor signaling in vascular smooth muscle cell proliferation? Circulation research 2006 Dec 8;99(12):1287-9
  10. Yook JI, Li XY, Ota I, Fearon ER, Weiss SJ
    Wnt-dependent regulation of the E-cadherin repressor snail. The Journal of biological chemistry 2005 Mar 25;280(12):11740-8
  11. Doble BW, Woodgett JR
    Role of glycogen synthase kinase-3 in cell fate and epithelial-mesenchymal transitions. Cells, tissues, organs 2007;185(1-3):73-84
  12. Stemmer V, de Craene B, Berx G, Behrens J
    Snail promotes Wnt target gene expression and interacts with beta-catenin. Oncogene 2008 Aug 28;27(37):5075-80
  13. Conacci-Sorrell M, Simcha I, Ben-Yedidia T, Blechman J, Savagner P, Ben-Ze'ev A
    Autoregulation of E-cadherin expression by cadherin-cadherin interactions: the roles of beta-catenin signaling, Slug, and MAPK. The Journal of cell biology 2003 Nov 24;163(4):847-57
  14. Sakai D, Tanaka Y, Endo Y, Osumi N, Okamoto H, Wakamatsu Y
    Regulation of Slug transcription in embryonic ectoderm by beta-catenin-Lef/Tcf and BMP-Smad signaling. Development, growth & differentiation 2005 Sep;47(7):471-82
  15. Kim K, Lu Z, Hay ED
    Direct evidence for a role of beta-catenin/LEF-1 signaling pathway in induction of EMT. Cell biology international 2002;26(5):463-76
  16. Vainio SJ, Uusitalo MS
    A road to kidney tubules via the Wnt pathway. Pediatric nephrology (Berlin, Germany) 2000 Nov;15(1-2):151-6
  17. Park JS, Valerius MT, McMahon AP
    Wnt/beta-catenin signaling regulates nephron induction during mouse kidney development. Development (Cambridge, England) 2007 Jul;134(13):2533-9
  18. Lyons JP, Mueller UW, Ji H, Everett C, Fang X, Hsieh JC, Barth AM, McCrea PD
    Wnt-4 activates the canonical beta-catenin-mediated Wnt pathway and binds Frizzled-6 CRD: functional implications of Wnt/beta-catenin activity in kidney epithelial cells. Experimental cell research 2004 Aug 15;298(2):369-87

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