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Molecular and Cellular Biology, October 2003, p. 6909-6921, Vol. 23, No. 19
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.19.6909-6921.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Functions of the Ectodomain and Cytoplasmic Tyrosine Phosphatase Domains of Receptor Protein Tyrosine Phosphatase Dlar In Vivo

Neil X. Krueger,^1,2 R. Sreekantha Reddy,^1,2 Karl Johnson,^3,4,5 Jack Bateman,^3,4,5 Nancy Kaufmann,^3,4,5 Daniella Scalice,^3,4,5 David Van Vactor,^3,4,5 and Haruo Saito^1,2,6*

Dana-Farber Cancer Institute,¹ Department of Biological Chemistry and Molecular Pharmacology,² Department of Cell Biology,³ Program in Neuroscience,⁴ Dana-Farber Cancer Institute/Harvard Cancer Center, Harvard Medical School, Boston, Massachusetts 02115,⁵ Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo 108-8639, Japan⁶

Received 12 May 2003/ Accepted 18 June 2003

The receptor protein tyrosine phosphatase (PTPase) Dlar has an ectodomain consisting of three immunoglobulin (Ig)-like domains and nine fibronectin type III (FnIII) repeats and a cytoplasmic domain consisting of two PTPase domains, membrane-proximal PTP-D1 and C-terminal PTP-D2. A series of mutant Dlar transgenes were introduced into the Drosophila genome via P-element transformation and were then assayed for their capacity to rescue phenotypes caused by homozygous loss-of-function genotypes. The Ig-like domains, but not the FnIII domains, are essential for survival. Conversely, the FnIII domains, but not the Ig-like domains, are required during oogenesis, suggesting that different domains of the Dlar ectodomain are involved in distinct functions during Drosophila development. All detectable PTPase activity maps to PTP-D1 in vitro. The catalytically inactive mutants of Dlar were able to rescue Dlar^-/- lethality nearly as efficiently as wild-type Dlar transgenes, while this ability was impaired in the PTP-D2 deletion mutants DlarPTP-D2 and Dlar^bypass. Dlar-C1929S, in which PTP-D2 has been inactivated, increases the frequency of bypass phenotype observed in Dlar^-/- genotypes, but only if PTP-D1 is catalytically active in the transgene. These results indicate multiple roles for PTP-D2, perhaps by acting as a docking domain for downstream elements and as a regulator of PTP-D1.

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* Corresponding author. Mailing address: Institute of Medical Science, University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan. Phone: 81-3-5449-5505. Fax: 81-3-5449-5701. E-mail: H-saito{at}ims.u-tokyo.ac.jp.

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Molecular and Cellular Biology, October 2003, p. 6909-6921, Vol. 23, No. 19
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.19.6909-6921.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

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