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J. Biol. Chem., Vol. 280, Issue 2, 1603-1612, January 14, 2005

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The Conserved Immunoglobulin Domain Controls the Subcellular Localization of the Homophilic Adhesion Receptor Protein-tyrosine Phosphatase µ^*

Robert L. Del Vecchio and Nicholas K. Tonks

From the Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724

The receptor protein-tyrosine phosphatase µ (PTPµ) is a homophilic adhesion protein thought to regulate cell-cell adhesion in the vascular endothelium through dephosphorylation of cell junction proteins. In subconfluent cell cultures, PTPµ resides in an intracellular membrane pool; however, as culture density increases and cell contacts form, the phosphatase localizes to sites of cell-cell contact, and its expression level increases. These characteristics of PTPµ, which are consistent with a role in cell-cell adhesion, suggest that control of subcellular localization is an important mechanism to regulate the function of this phosphatase. To gain a better understanding of how PTPµ is regulated, we examined the importance of the conserved immunoglobulin domain, containing the homophilic binding site, in control of the localization of the enzyme. Deletion of the immunoglobulin domain impaired localization of PTPµ to the cell-cell contacts in endothelial and epithelial cells. In addition, deletion of the immunoglobulin domain affected the distribution of PTPµ in subconfluent endothelial cells when homophilic binding to another PTPµ molecule on an apposing cell was not possible, resulting in an accumulation of the mutant phosphatase at the cell surface with a concentration at the cell periphery in the region occupied by focal adhesions. This aberrant localization correlated with reduced survival and alterations in normal focal adhesion and cytoskeleton morphology. This study therefore illustrates the critical role of the immunoglobulin domain in regulation of the localization of PTPµ and the importance of such control for the maintenance of normal cell physiology.

Received for publication, September 3, 2004 , and in revised form, October 13, 2004.

^* This work was supported by National Institutes of Health Grant GM55989. 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.

To whom correspondence should be addressed: Cold Spring Harbor Lab., 1 Bungtown Rd., Cold Spring Harbor, NY 11724. Tel.: 516-367-8846; Fax: 516-367-6812; E-mail: tonks{at}cshl.edu.

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