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VCAM-1 Activation of Endothelial Cell Protein Tyrosine Phosphatase 1B¹

Tracy L. Deem^2,,, Hiam Abdala-Valencia^2,*, and Joan M. Cook-Mills^3,*,

^* Allergy-Immunology Division, Northwestern University, Feinberg School of Medicine, Chicago, IL 60611; Department of Pathology and Laboratory Medicine, University of Cincinnati, Cincinnati, OH 45267; and Cardiovascular Research Center, University of Virginia, Charlottesville, VA 22908

Lymphocytes migrate from the blood into tissue by binding to and migrating across endothelial cells. One of the endothelial cell adhesion molecules that mediate lymphocyte binding is VCAM-1. We have reported that binding to VCAM-1 activates endothelial cell NADPH oxidase for the generation of reactive oxygen species (ROS). The ROS oxidize and stimulate an increase in protein kinase C (PKC) activity. Furthermore, these signals are required for VCAM-1-dependent lymphocyte migration. In this report, we identify a role for protein tyrosine phosphatase 1B (PTP1B) in the VCAM-1 signaling pathway. In primary cultures of endothelial cells and endothelial cell lines, Ab cross-linking of VCAM-1 stimulated an increase in serine phosphorylation of PTP1B, the active form of PTP1B. Ab cross-linking of VCAM-1 also increased activity of PTP1B. This activation of PTP1B was downstream of NADPH oxidase and PKC in the VCAM-1 signaling pathway as determined with pharmacological inhibitors and antisense approaches. In addition, during VCAM-1 signaling, ROS did not oxidize endothelial cell PTP1B. Instead PTP1B was activated by serine phosphorylation. Importantly, inhibition of PTP1B activity blocked VCAM-1-dependent lymphocyte migration across endothelial cells. In summary, VCAM-1 activates endothelial cell NADPH oxidase to generate ROS, resulting in oxidative activation of PKC and then serine phosphorylation of PTP1B. This PTP1B activity is necessary for VCAM-1-dependent transendothelial lymphocyte migration. These data show, for the first time, a function for PTP1B in VCAM-1-dependent lymphocyte migration.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This study was supported by National Institutes of Health Grant RO1 HL69428 (to J.M.C.-M.).

² T.L.D. and H.A.-V. are co-first authors.

³ Address correspondence and reprint requests to Dr. Joan M. Cook-Mills, Allergy-Immunology Division, Northwestern University, Feinberg School of Medicine, McGaw-304, 240 East Huron, Chicago, IL 60611. E-mail address: j-cook-mills{at}northwestern.edu

⁴ Abbreviations used in this paper: ROS, reactive oxygen species; MMP, matrix metalloproteinase; PKC, protein kinase C; HMEC, human microvascular endothelial cell; PTP, protein tyrosine phosphatase; DN, dominant-negative; IAA, iodoacetic acid.

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