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A more recent version of this article appeared on September 1, 2003
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Submitted on February 12, 2003
Revised on May 10, 2003
Accepted on May 22, 2003
1 Department of Structural Analysis, National
Cardiovascular Center Research Institute, Suita, Osaka 565-8565, Japan
2 Department of Oncogene Research, Research Institute for
Microbial Diseases, Osaka University, Osaka 565-0871, Japan
3 Department of Structural Analysis, National Cardiovascular Center Research Institute, Suita, Osaka 565-8565, Japan
* Corresponding author. E-mail address: nmochizu{at}ri.ncvc.go.jp.
Platelet endothelial adhesion molecule-1 (PECAM-1) is a part of intercellular junctions and triggers intracellular signaling cascades upon homophilic binding. The intracellular domain of PECAM-1 is tyrosine phosphorylated upon homophilic engagement. However, it remains unclear which tyrosine kinase phosphorylates PECAM-1. We sought to isolate tyrosine kinases responsible for PECAM-1 phosphorylation and identified Fer as a candidate, based on expression cloning. Fer kinase specifically phosphorylated PECAM-1 at the immunoreceptor tyrosine-based inhibitory motif (ITIM). Notably, Fer induced tyrosine phosphorylation of SHP-2, which is known to bind to the ITIM of PECAM-1, and Fer also induced tyrosine phosphorylation of Gab1. Engagement-dependent PECAM-1 phosphorylation was inhibited by the overexpression of a kinase-inactive mutant of Fer, suggesting that Fer is responsible for the tyrosine phosphorylation upon PECAM-1 engagement. Furthermore, by using green fluorescent protein-tagged Fer and a time-lapse fluorescent microscope, we found that Fer localized at microtubules in polarized and motile vascular endothelial cells. Fer was dynamically associated with growing microtubules in the direction of cell-cell contacts, where p120catenin, which is known to associate with Fer, colocalized with PECAM-1. These results suggest that Fer localized on microtubules may play an important role in phosphorylation of PECAM-1, possibly through its association with p120catenin at nascent cell-cell contacts.
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