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First published online June 28, 2004
doi: 10.1242/10.1242/jcs.01174
Research Article |
1 Department of Biological Sciences, The University of Iowa, Iowa City, IA 52242, USA
2 Department of Biochemistry, Room 641 Botterell Hall, Queen's University, Kingston, Ontario, K7L 3N6, Canada
3 Department of Pathology, Division of Cancer Biology and Genetics, Room A309 Botterell Hall, Queen's University Cancer Research Institute, Kingston, Ontario, K7L 3N6, Canada
4 Laboratory of Cell Adhesion and Metastasis, Mayo Clinic, Griffin Cancer Research Building, 4500 San Pablo Road, Jacksonville, FL 32224, USA
* Author for correspondence (e-mail: jack-lilien{at}uiowa.edu)
Accepted 24 February 2004
The function of Type 1, classic cadherins depends on their association with the actin cytoskeleton, a connection mediated by 
- and ß-catenin. The phosphorylation state of ß-catenin is crucial for its association with cadherin and thus the association of cadherin with the cytoskeleton. We now show that the phosphorylation of ß-catenin is regulated by the combined activities of the tyrosine kinase Fer and the tyrosine phosphatase PTP1B. Fer phosphorylates PTP1B at tyrosine 152, regulating its binding to cadherin and the continuous dephosphorylation of ß-catenin at tyrosine 654. Fer interacts with cadherin indirectly, through p120ctn. We have mapped the interaction domains of Fer and p120ctn and peptides corresponding to these sequences release Fer from p120ctn in vitro and in live cells, resulting in loss of cadherin-associated PTP1B, an increase in the pool of tyrosine phosphorylated ß-catenin and loss of cadherin adhesion function. The effect of the peptides is lost when a ß-catenin mutant with a substitution at tyrosine 654 is introduced into cells. Thus, Fer phosphorylates PTP1B at tyrosine 152 enabling it to bind to the cytoplasmic domain of cadherin, where it maintains ß-catenin in a dephosphorylated state. Cultured fibroblasts from mouse embryos targeted with a kinase-inactivating ferD743R mutation have lost cadherin-associated PTP1B and ß-catenin, as well as localization of cadherin and ß-catenin in areas of cell-cell contacts. Expression of wild-type Fer or culture in epidermal growth factor restores the cadherin complex and localization at cell-cell contacts.
Key words: Cadherin, Fer tyrosine kinase, PTP1B tyrosine phosphatase, ß-Catenin, Adhesion
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