Tyrosine residues 654 and 670 in beta-catenin are crucial in regulation of Met-beta-catenin interactions.
beta-Catenin, a key component of the canonical Wnt pathway, is also regulated by tyrosine phosphorylation that regulates its association to E-cadherin. Previously, we reported its association with the hepatocyte growth factor (HGF) receptor Met at the membrane. HGF induced Met-beta-catenin dissociation and nuclear translocation of beta-catenin, which was tyrosine-phosphorylation-dependent. Here, we further investigate the Met-beta-catenin interaction by selectively mutating several tyrosine residues, alone or in combination, in beta-catenin. The mutants were subcloned into FLAG-CMV vector and stably transfected into rat hepatoma cells, which were treated with HGF. All single or double-mutant-transfected cells continued to show HGF-induced nuclear translocation of FLAG-beta-catenin except the mutations affecting 654 and 670 simultaneously (Y654/670F), which coincided with the lack of formation of beta-catenin-TCF complex and DNA synthesis, in response to the HGF treatment. In addition, the Y654/670F-transfected cells also showed no phosphorylation of beta-catenin or dissociation from Met in response to HGF. Thus, intact 654 and 670 tyrosine residues in beta-catenin are crucial in HGF-mediated beta-catenin translocation, activation and mitogenesis.
Zeng
Gang
G
Department of Pathology (CMP), University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.
Apte
Udayan
U
Micsenyi
Amanda
A
Bell
Aaron
A
Monga
Satdarshan P S
SP
D000818:Animals; D015820:Cadherins / Q000378:metabolism; D002460:Cell Line; D049109:Cell Proliferation; D017228:Hepatocyte Growth Factor / Q000378:metabolism; D006801:Humans; D016297:Mutagenesis, Site-Directed; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism*; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D051820:TCF Transcription Factors / Q000378:metabolism; D014443:Tyrosine / Q000378:metabolism*; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
D015820:Cadherins; D011993:Recombinant Fusion Proteins; D051820:TCF Transcription Factors; D051176:beta Catenin; D014443:Tyrosine; D017228:Hepatocyte Growth Factor; D019859:Proto-Oncogene Proteins c-met