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A more recent version of this article appeared on August 1, 2006
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Submitted on March 13, 2006
Revised on May 1, 2006
Accepted on May 8, 2006
*The M. Dyson Vision Research Institute and the Graduate Program in Pharmacology at Cornell University Medical College, New York, NY 10021
Monitoring Editor: Ben Margolis
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 (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: (i) 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. (ii) 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.
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