BCL9-2 binds Arm/beta-catenin in a Tyr142-independent manner and requires Pygopus for its function in Wg/Wnt signaling.
The Wingless (Wg)/Wnt signal transduction pathway controls fundamental processes during animal development. Deregulation of the Wg/Wnt pathway has been causally linked to several forms of cancer, most notably to colorectal cancer. In response to Wg/Wnt signaling, Armadillo/beta-catenin associates in the nucleus with DNA bound TCF and several co-factors, among them Legless/BCL9, which provides a link to Pygopus. Recently, the second vertebrate homologue of Legless, BCL9-2 (or B9L), was characterized and proposed to mediate Wnt signaling in a Pygopus-independent manner, by binding to a Tyrosine-142-phosphorylated form of beta-catenin. Here we examine the role of Tyrosine-142 phosphorylation in several assays and find that it is neither important for the recruitment of BCL9-2, nor for the transcriptional activity of beta-catenin in cultured mammalian cells, nor in Drosophila for Wg signaling activity in vivo. Furthermore, we demonstrate that BCL9-2 can functionally replace Lgs both in cultured cells as well as in vivo and that this rescue activity depends on the ability of BCL9-2 to bind Pygo. Our results do not show a significant functional difference between BCL9-2 and BCL9 but rather suggest that the two proteins represent evolutionary duplicates of Legless, which have acquired distinct expression patterns while acting in a largely redundant manner.
Hoffmans
Raymond
R
Institut für Molekularbiologie, Universität Zürich, Winterthurerstrasse 190, CH-8057 Zürich, Switzerland.
Basler
Konrad
K
D000818:Animals; D030801:Animals, Genetically Modified; D051186:Armadillo Domain Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D001483:Base Sequence; D001665:Binding Sites; D002460:Cell Line; D004247:DNA / Q000235:genetics; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000196:embryology / Q000235:genetics / Q000378:metabolism; D019143:Evolution, Molecular; D006801:Humans; D066298:In Vitro Techniques; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D016297:Mutagenesis, Site-Directed; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D011485:Protein Binding; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D020798:Two-Hybrid System Techniques; D014443:Tyrosine / Q000737:chemistry; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism*; D051155:Wnt1 Protein; D051176:beta Catenin / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
D051186:Armadillo Domain Proteins; D029721:Drosophila Proteins; D047908:Intracellular Signaling Peptides and Proteins; C453403:Lgs protein, Drosophila; D009363:Neoplasm Proteins; D011518:Proto-Oncogene Proteins; D011994:Recombinant Proteins; D051153:Wnt Proteins; D051155:Wnt1 Protein; D051176:beta Catenin; C453400:pygo protein, Drosophila; C074622:wg protein, Drosophila; D014443:Tyrosine; D004247:DNA