pangolinencodes a Lef-1 homologue that acts downstream of Armadillo to transduce the Wingless signal in Drosophila

Abstract

Members of the Wnt/Wingless (Wg) family of signalling proteins organize many aspects of animal development by regulating the expression of particular target genes in responding cells. Recent biochemical studies indicate that the vertebrate HMG-domain proteins Lef-1 and XTcf-3 can physically interact with beta-catenin, a homologue of Drosophila Armadillo (Arm), the most downstream component known in the Wnt signal transduction pathway. However, these studies do not address whether the endogenous Lef/Tcf family members are required in vivo to transduce Wnt signals. Using genetic methods in Drosophila, we define a new segment polarity gene, pangolin (pan), and show that its product is required in vivo for Wg signal transduction in embryos and in developing adult tissues. In addition, we show that pan encodes a Lef/Tcf homologue and provide evidence that its protein product binds to the beta-catenin homologue Armadillo in vivo. Finally, we demonstrate that Pan functions downstream of Arm to transduce the Wg signal. Thus, our results indicate that Pan is an essential component of the Wg transduction pathway and suggest that it acts directly to regulate gene transcription in response to Wg signalling.

Atherosclerotic Calcification: Wnt Is the Hint

“…As a result, β‐catenin is stabilized, accumulates in the cytoplasm, and subsequently translocates to the nucleus 73. In the nucleus, β‐catenin associates with members of the lymphoid enhancer‐binding factor/T‐cell factor family of transcription factors and several other factors, enabling this complex to act as a transcriptional activator or repressor of Wnt target genes 76, 79, 80. Canonical Wnt signaling is illustrated in Figure 1.…”

eyelidantagonizes wingless signaling during Drosophiladevelopment and has homology to the Bright family of DNA-binding proteins

“…Active, unphosphorylated Arm accumulates in the cytoplasm and nucleus, whereas the phosphorylated form is restricted to adherens junctions (Peifer et al 1994a,b;Orsulic and Peifer 1996). Pan, a Drosophila homolog of the HMG box protein Lef-1, is a good candidate to act in combination with Arm to activate target genes such as en or Ubx (Brunner et al 1997;Riese et al 1997;van de Wetering et al 1997). These target genes are the only other known nuclear effectors of wg, and because their expression is induced by Wg, they cannot be directly involved in transducing the signal.…”

“…In vertebrates, adenomatous polyposis coli (APC), a large protein with multiple sequence repeats present also in Arm, and the high mobility group (HMG) box proteins, Tcf-1 and LEF-1, have been proposed to act in Wnt signaling because of their molecular or functional interactions with the Arm homolog ␤-catenin or the sgg homolog GSK3 (Rubinfeld et al 1993(Rubinfeld et al , 1996Su et al 1993;Behrens et al 1996;Huber et al 1996;Molenaar et al 1996). A Drosophila Tcf-1 homolog, pangolin (pan), has been shown recently to be an essential component of the Wg pathway and to bind to the Arm protein (Brunner et al 1997;Riese et al 1997;van de Wetering et al 1997). However, the Drosophila APC homolog is not expressed at the time when wg acts on embryonic segmentation (Hayashi et al 1997).…”

“…However, the Drosophila APC homolog is not expressed at the time when wg acts on embryonic segmentation (Hayashi et al 1997). The Arm-Pan complex may activate the transcription of Wg target genes (Brunner et al 1997;van de Wetering et al 1997) such as engrailed (en) in the embryonic epidermis (DiNardo et al 1988), Ultrabithorax in the midgut (Riese et al 1997), achaete and cut at the wing margin (Couso et al 1994), and optomotor-blind, nubbin, vestigial, and distalless in the wing pouch (Diaz-Benjumea and Cohen 1995;Grimm and Pflugfelder 1996;Ng et al 1996;Zecca et al 1996). All of these genes encode transcription factors that mediate the subsequent effects of Wg.…”

P53 levels determine outcome during β-catenin tumor initiation and metastasis in the mammary gland and male germ cells

“…In response to extracellular Wnt, a signal is transduced through the Frizzled receptor to disheveled leading to disruption of the b-catenin/APC/Axin/GSK3b complex. Subsequently, b-catenin accumulates and enters the nucleus where it associates with Tcf/Lef transcription factors and activates target genes (Behrens et al, 1996;Molenaar et al, 1996;Brunner et al, 1997;van de Wetering et al, 1997). Aberrant stabilization of bcatenin is observed in a variety of cancers, owing to mutations in APC, Axin or within b-catenin itself that result in a block of GSK3b phosphorylation and prevent the degradation cascade.…”