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Mol Cell Biol, May 1998, p. 2608-2616, Vol. 18, No. 5
0270-7306/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

The Second Catalytic Domain of Protein Tyrosine Phosphatase delta  (PTPdelta ) Binds to and Inhibits the First Catalytic Domain of PTPsigma

Megan J. Wallace, Christopher Fladd, Jane Batt, and Daniela Rotin*

Division of Respiratory Research, The Hospital for Sick Children, Toronto, Ontario M5G 1X8, and Department of Biochemistry, University of Toronto, Toronto, Ontario M5S 1A8, Canada

Received 23 June 1997/Returned for modification 12 August 1997/Accepted 19 February 1998

The LAR family protein tyrosine phosphatases (PTPs), including LAR, PTPdelta , and PTPsigma , are transmembrane proteins composed of a cell adhesion molecule-like ectodomain and two cytoplasmic catalytic domains: active D1 and inactive D2. We performed a yeast two-hybrid screen with the first catalytic domain of PTPsigma (PTPsigma -D1) as bait to identify interacting regulatory proteins. Using this screen, we identified the second catalytic domain of PTPdelta (PTPdelta -D2) as an interactor of PTPsigma -D1. Both yeast two-hybrid binding assays and coprecipitation from mammalian cells revealed strong binding between PTPsigma -D1 and PTPdelta -D2, an association which required the presence of the wedge sequence in PTPsigma -D1, a sequence recently shown to mediate D1-D1 homodimerization in the phosphatase RPTPalpha . This interaction was not reciprocal, as PTPdelta -D1 did not bind PTPsigma -D2. Addition of a glutathione S-transferase (GST)-PTPdelta -D2 fusion protein (but not GST alone) to GST-PTPsigma -D1 led to ~50% inhibition of the catalytic activity of PTPsigma -D1, as determined by an in vitro phosphatase assay against p-nitrophenylphosphate. A similar inhibition of PTPsigma -D1 activity was obtained with coimmunoprecipitated PTPdelta -D2. Interestingly, the second catalytic domains of LAR (LAR-D2) and PTPsigma (PTPsigma -D2), very similar in sequence to PTPdelta -D2, bound poorly to PTPsigma -D1. PTPdelta -D1 and LAR-D1 were also able to bind PTPdelta -D2, but more weakly than PTPsigma -D1, with a binding hierarchy of PTPsigma -D1>>PTPdelta -D1>LAR-D1. These results suggest that association between PTPsigma -D1 and PTPdelta -D2, possibly via receptor heterodimerization, provides a negative regulatory function and that the second catalytic domains of this and likely other receptor PTPs, which are often inactive, may function instead to regulate the activity of the first catalytic domains.

* Corresponding author. Mailing address: The Hospital for Sick Children, 555 University Avenue, Toronto, Ontario, Canada M5G 1X8. Phone: (416) 813-5098. Fax: (416) 813-5771. E-mail: drotin{at}sickkids.on.ca.

Mol Cell Biol, May 1998, p. 2608-2616, Vol. 18, No. 5
0270-7306/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.


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