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J Biol Chem, Vol. 275, Issue 20, 15350-15356, May 19, 2000

Intramolecular Interactions between the Juxtamembrane Domain and Phosphatase Domains of Receptor Protein-tyrosine Phosphatase RPTPµ
REGULATION OF CATALYTIC ACTIVITY^*

Elles Feiken, Ingrid van Etten, Martijn F. B. G. Gebbink, Wouter H. Moolenaar^§, and Gerben C. M. Zondag

From the Division of Cellular Biochemistry, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands

RPTPµ is a receptor-like protein-tyrosine phosphatase (RPTP) whose ectodomain mediates homotypic cell-cell interactions. The intracellular part of RPTPµ contains a relatively long juxtamembrane domain (158 amino acids; aa) and two conserved phosphatase domains (C1 and C2). The membrane-proximal C1 domain is responsible for the catalytic activity of RPTPµ, whereas the membrane-distal C2 domain serves an unknown function. The regulation of RPTP activity remains poorly understood, although dimerization has been proposed as a general mechanism of inactivation. Using the yeast two-hybrid system, we find that the C1 domain binds to an N-terminal noncatalytic region in RPTPµ, termed JM (aa 803-955), consisting of a large part of the juxtamembrane domain (120 aa) and a small part of the C1 domain (33 aa). When co-expressed in COS cells, the JM polypeptide binds to both the C1 and the C2 domain. Strikingly, the isolated JM polypeptide fails to interact with either full-length RPTPµ or with truncated versions of RPTPµ that contain the JM region, consistent with the JM-C1 and JM-C2 interactions being intramolecular rather than intermolecular. Furthermore, we find that large part of the juxtamembrane domain (aa 814-922) is essential for C1 to be catalytically active. Our findings suggest a model in which RPTPµ activity is regulated by the juxtamembrane domain undergoing intramolecular interactions with both the C1 and C2 domain.

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^* This work was supported by the Dutch Cancer Society.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Present address: Laboratory of Medical Oncology, Dept. of Internal Medicine, University Medical Center, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands.

^§ To whom correspondence should be addressed. Tel.: 31-20-512-1971; Fax: 31-20-512-1989; E-mail: wmoolen@nki.nl.

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Copyright © 2000 by The American Society for Biochemistry and Molecular Biology, Inc.

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