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Molecular and Cellular Biology, August 2000, p. 5917-5929, Vol. 20, No. 16
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Receptor-Like Protein Tyrosine Phosphatase  Homodimerizes on the Cell Surface

Guoqiang Jiang,^1, Jeroen den Hertog,² and Tony Hunter^1,*

Molecular Biology and Virology Laboratory, The Salk Institute for Biological Studies, La Jolla, California 92037,¹ and Hubrecht Laboratory, Netherlands Institute for Developmental Biology, 3584 CT Utrecht, The Netherlands²

Received 28 December 1999/Returned for modification 13 March 2000/Accepted 12 May 2000

We reported previously that the N-terminal D1 catalytic domain of receptor protein-tyrosine phosphatase  (RPTP) forms a symmetrical, inhibited dimer in a crystal structure, in which a helix-turn-helix wedge element from one monomer is inserted into the catalytic cleft of the other monomer. Previous functional studies also suggested that dimerization inhibits the biological activity of a CD45 chimeric RPTP and the catalytic activity of an isolated RPTP D1 catalytic domain. Most recently, we have also shown that enforced dimerization inhibits the biological activity of full-length RPTP in a wedge-dependent manner. The physiological significance of such inhibition is unknown, due to a lack of understanding of how RPTP dimerization is regulated in vivo. In this study, we show that transiently expressed cell surface RPTP exists predominantly as homodimers, suggesting that dimerization-mediated inhibition of RPTP biological activity is likely to be physiologically relevant. Consistent with our published and unpublished crystallographic data, we show that mutations in the wedge region of D1 catalytic domain and deletion of the entire D2 catalytic domain independently reduced but did not abolish RPTP homodimerization, suggesting that both domains are critically involved but that neither is essential for homodimerization. Finally, we also provide evidence that both the RPTP extracellular domain and the transmembrane domain were independently able to homodimerize. These results lead us to propose a zipper model in which inactive RPTP dimers are stabilized by multiple, relatively weak dimerization interfaces. Dimerization in this manner would provide a potential mechanism for negative regulation of RPTP. Such RPTP dimers could be activated by extracellular ligands or intracellular binding proteins that induce monomerization or by intracellular signaling events that induce an open conformation of the dimer.

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^* Corresponding author. Mailing address: Molecular Biology and Virology Laboratory, The Salk Institute for Biological Studies, 10010 North Torrey Pines Rd., La Jolla, CA 92037. Phone: (858) 453-4100, x1385. Fax: (858) 456-4765. E-mail: Hunter{at}salk.edu.

Present address: Molecular Endocrinology and Metabolic Disorders, Merck & Co., Inc., Rahway, NJ 07065.

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Molecular and Cellular Biology, August 2000, p. 5917-5929, Vol. 20, No. 16
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

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