Numb regulates cell-cell adhesion and polarity in response to tyrosine kinase signalling.
Epithelial-mesenchymal transition (EMT), which can be caused by aberrant tyrosine kinase signalling, marks epithelial tumour progression and metastasis, yet the underlying molecular mechanism is not fully understood. Here, we report that Numb interacts with E-cadherin (E-cad) through its phosphotyrosine-binding domain (PTB) and thereby regulates the localization of E-cad to the lateral domain of epithelial cell-cell junction. Moreover, Numb engages the polarity complex Par3-aPKC-Par6 by binding to Par3 in polarized Madin-Darby canine kidney cells. Intriguingly, after Src activation or hepatocyte growth factor (HGF) treatment, Numb decouples from E-cad and Par3 and associates preferably with aPKC-Par6. Binding of Numb to aPKC is necessary for sequestering the latter in the cytosol during HGF-induced EMT. Knockdown of Numb by small hairpin RNA caused a basolateral-to-apicolateral translocation of E-cad and beta-catenin accompanied by elevated actin polymerization, accumulation of Par3 and aPKC in the nucleus, an enhanced sensitivity to HGF-induced cell scattering, a decrease in cell-cell adhesion, and an increase in cell migration. Our work identifies Numb as an important regulator of epithelial polarity and cell-cell adhesion and a sensor of HGF signalling or Src activity during EMT.
Wang
Zezhou
Z
Department of Biochemistry and the Siebens-Drake Medical Research Institute, Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario, Canada.
Sandiford
Shelley
S
Wu
Chenggang
C
Li
Shawn Shun-Cheng
SS
D020816:Amino Acid Motifs; D000818:Animals; D015820:Cadherins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D002448:Cell Adhesion; D002460:Cell Line; D002465:Cell Movement; D016764:Cell Polarity; D004285:Dogs; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D008565:Membrane Proteins / Q000737:chemistry / Q000378:metabolism*; D008969:Molecular Sequence Data; D017354:Point Mutation; D011493:Protein Kinase C / Q000032:analysis / Q000378:metabolism; D017434:Protein Structure, Tertiary; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D016415:Sequence Alignment; D015398:Signal Transduction; D014443:Tyrosine / Q000378:metabolism; D051176:beta Catenin / Q000032:analysis / Q000378:metabolism
D015820:Cadherins; D008565:Membrane Proteins; D051176:beta Catenin; D014443:Tyrosine; D011505:Protein-Tyrosine Kinases; C115015:PKC-3 protein; D011493:Protein Kinase C