Fight for dTcf Binding
Signal transduction pathways play a pivotal role in growth and patterning various tissues in animals and some of these pathways are very much conserved in evolution from Sponges to Humans. Wnt/Wingless (Wg) and TGFβ/BMP/dpp are perfect examples of highly conserved signaling pathways in evolution and any aberrant functioning of these vital pathways will lead to various cancers.To get more insights into aberrant development and cancers that results when regulation of signalling is disrupted, Esther M. Verheyen’s group studied the mechanism of interaction between Drosophila Wg and BMP signaling in which Wg target gene expression is antagonized by BMP signaling. Results of their latest work on Competition between Mad and Armadillo/β-Catenin for dTcf Binding was published in PLOS one open access journal on December 9,2008.
Wingless signaling in brief :
Wingless (Wg) signaling is mediated by the DNA-binding transcription factor, dTcf, and its co-activator β-catenin/Armadillo (Arm) . In the absence of Wg signaling, cytoplasmic Arm levels are kept low through continuous proteasome-mediated degradation, which is controlled by a complex of Zw3, APC and Axin. When wg is bound to Frizzled receptor , Zw3 kinase activity is down regulated allowing arm to escape degradation and get stabilized in cytooplasam. Later arm enters nucleus and forms a complex with dTCF and activate various wg targets genes such as achaete (ac), senseless (sens) and distal-less (dll) ,which organize the D/V boundary of the wing and contribute to adult features such as the wing margin.
TGFβ/BMP/dpp signaling pathway in brief :
The best-characterized TGFβ ligand in Drosophila is Decapentaplegic (Dpp), a member of the BMP family of ligands . Upon Dpp ligand binding and receptor oligomerization, the type II receptor Punt activates the serine/threonine kinase activity of the type I receptor Thickveins (Tkv). Tkv then phosphorylates the receptor-regulated Smad, Mothers against Dpp (Mad), which then allows it to bind the co-Smad Medea (Med), translocate to the nucleus and bind DNA to activate gene expression.
Important Findings:
The wing of fruit fly “Drosophila melanogaster” has served as tissue of choice of various scientists as it gives many options to dissect various signaling molecules in development. Roles of both wg and dpp are quite essential in wing development as they play vital roles in assigning Dorso/ventro (DV) and Anterior/posterior (AP) organizer respectively.(For a detailed account on wg and dpp in wing morphogenesis read the review “Morphogens, their identification and regulation” by Tabata and Takei
Cross talk between both wg and dpp pathways have been described in various systems and in this particular study Verheyen’s group led by Yi Arial Zeng decided to have a careful look at wing patterning phenotypes that occur upon modulation of Wg and Dpp pathways.Using various genetic,molecular and biochemical tools authors have shown that both the nuclear effectors of wg and dpp pathways in arm and mad compete for dTCF. They come up with a mechanism involved between wg and dpp in wing development,where Wg target gene expression is antagonized by BMP signaling ,which are based on following invivo and invitro results :
1) High levels of both an activated BMP receptor and the BMP effector Mad can inhibit the expression of Wg target genes.
2) Loss of mad can induce Wg target gene expression.They checked for four targets of wg signaling,which are nemo (nmo) ,Distalless( dll), Senseless (sens)and achaete (ac)
3) Ectopic expression in vivo of the Wg transcription factor dTcf is able to suppress the inhibitory effect caused by ectopic Mad.
4) In vitro binding studies revealed competition for dTcf binding between Mad and the Wnt effector β-catenin/Armadillo (Arm)
All these results supports the view that BMP pathway components can repress Wg target gene expression by influencing the binding of Arm and dTcf. Finally, just before concluding I suggest all of you to go through the full version of paper available on Plos one as this work happens to be a perfect example of nice amalgam of genetics,molecular and biochemical worK.
Citation, image credit and reference :
Zeng YA, Rahnama M, Wang S, Lee W, Verheyen EM (2008) Inhibition of Drosophila Wg Signaling Involves Competition between Mad and Armadillo/β-Catenin for dTcf Binding. PLoS ONE 3(12): e3893. doi:10.1371/journal.pone.0003893
Related Posts:
If you liked what you just read, you may want to subscribe to my
RSS FEED
Thanks for visiting!
Leave your response!