PAR1b promotes cell-cell adhesion and inhibits dishevelled-mediated transformation of Madin-Darby canine kidney cells.
Mammalian Par1 is a family of serine/threonine kinases comprised of four homologous isoforms that have been associated with tumor suppression and differentiation of epithelial and neuronal cells, yet little is known about their cellular functions. In polarizing kidney epithelial (Madin-Darby canine kidney [MDCK]) cells, the Par1 isoform Par1b/MARK2/EMK1 promotes the E-cadherin-dependent compaction, columnarization, and cytoskeletal organization characteristic of differentiated columnar epithelia. Here, we identify two functions of Par1b that likely contribute to its role as a tumor suppressor in epithelial cells. 1) The kinase promotes cell-cell adhesion and resistance of E-cadherin to extraction by nonionic detergents, a measure for the association of the E-cadherin cytoplasmic domain with the actin cytoskeleton, which is critical for E-cadherin function. 2) Par1b attenuates the effect of Dishevelled (Dvl) expression, an inducer of wnt signaling that causes transformation of epithelial cells. Although Dvl is a known Par1 substrate in vitro, we determined, after mapping the PAR1b-phosphorylation sites in Dvl, that PAR1b did not antagonize Dvl signaling by phosphorylating the wnt-signaling molecule. Instead, our data suggest that both proteins function antagonistically to regulate the assembly of functional E-cadherin-dependent adhesion complexes.
Elbert
Maya
M
Margaret M. Dyson Vision Research Institute and Graduate Program in Pharmacology, Cornell University Medical College, New York, NY 10021, USA.
Cohen
David
D
Müsch
Anne
A
D000199:Actins / Q000378:metabolism; D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000596:Amino Acids / Q000378:metabolism; D000818:Animals; D015820:Cadherins / Q000378:metabolism; D002448:Cell Adhesion; D016764:Cell Polarity; D002478:Cells, Cultured; D003599:Cytoskeleton / Q000378:metabolism; D000072261:Dishevelled Proteins; D004285:Dogs; D004847:Epithelial Cells / Q000166:cytology*; D015870:Gene Expression; D051379:Mice; D010641:Phenotype; D010750:Phosphoproteins / Q000378:metabolism*; D010766:Phosphorylation; D011485:Protein Binding; D044463:Receptor, PAR-1 / Q000172:deficiency / Q000378:metabolism*; D015398:Signal Transduction; D051153:Wnt Proteins / Q000378:metabolism
D000199:Actins; D048868:Adaptor Proteins, Signal Transducing; D000596:Amino Acids; D015820:Cadherins; D000072261:Dishevelled Proteins; D010750:Phosphoproteins; D044463:Receptor, PAR-1; D051153:Wnt Proteins