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Vol. 14, Issue 9, 3553-3564, September 2003

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Identification of Fer Tyrosine Kinase Localized on Microtubules as a Platelet Endothelial Cell Adhesion Molecule-1 Phosphorylating Kinase in Vascular Endothelial Cells

Naoko Kogata ^*, Michitaka Masuda ^*, Yuji Kamioka ^*, Akiko Yamagishi ^*, Akira Endo ^*, Masato Okada , and Naoki Mochizuki ^* 

^* Department of Structural Analysis, National Cardiovascular Center Research Institute, Suita, Osaka 565-8565, Japan; Department of Oncogene Research, Research Institute for Microbial Diseases, Osaka University, Osaka 565-0871, Japan

Submitted February 12, 2003; Revised May 10, 2003; Accepted May 22, 2003
Monitoring Editor: Richard Assoian

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. Notably, Fer induced tyrosine phosphorylation of SHP-2, which is known to bind to the immunoreceptor tyrosine-based inhibitory motif of PECAM-1, and Fer also induced tyrosine phosphorylation of Gab1 (Grb2-associated binder-1). 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.

Online version of this article contains video material for some figures. Online version is available at www.molbiolcell.org.

Corresponding author. E-mail address: nmochizu{at}ri.ncvc.go.jp. Abbreviations used: BAEC, bovine aortic endothelial cell; EGFP, enhanced green fluorescent protein; ERK, extracellular signal-regulated kinase; FBS, fetal bovine serum; FCH, Fps/Fes/Fer and CIP4 homology; Gab1, Grb2-associated binder-1; GFP, green fluorescent protein; HAEC, human aortic endothelial cell; IRES, internal ribosomal entry site; ITIM, immunoreceptor tyrosine-based inhibitory motif; KD, kinase defective; p120ctn, p120 catenin; PCR, polymerase chain reaction; PECAM-1, platelet endothelial cell adhesion molecule-1; SH, Src homology; WT, wild type.

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