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J. Biol. Chem., Vol. 279, Issue 49, 51013-51021, December 3, 2004

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Essential Domain of Receptor Tyrosine Phosphatase (RPTP) for Interaction with Helicobacter pylori Vacuolating Cytotoxin^*

Kinnosuke Yahiro, Akihiro Wada¶, Eiki Yamasaki¶, Masaaki Nakayama, Yoshito Nishi, Jyunzou Hisatsune, Naoko Morinaga, Jan Sap||, Masatoshi Noda, Joel Moss**, and Toshiya Hirayama

From the Department of Bacteriology, Institute of Tropical Medicine, Nagasaki University, Nagasaki 8528523, Japan, Department of Molecular Infectiology, Graduate School of Medicine, Chiba University, Chiba 2608670, Japan, ^¶PRESTO, Japan Science and Technology Corporation, Saitama 3320012, Japan, ^||Department of Pharmacology, New York University School of Medicine, New York, New York 10016-6481, and ^**Pulmonary-Critical Care Medicine Branch, NHLBI, National Institutes of Health, Bethesda, Maryland 20892-1590

Helicobacter pylori produces a potent exotoxin, VacA, which causes progressive vacuolation as well as gastric injury. Although VacA was able to interact with two receptor-like protein tyrosine phosphatases, RPTP and RPTP, RPTP was found to be responsible for gastric damage caused by VacA. To define the region of RPTP involved in VacA binding, we made mutants of human cDNA RPTP-B, a short receptor form of RPTP. Immunoprecipitation experiments to assess VacA binding to RPTP-B mutants indicated that five residues (QTTQP) at positions 747–751 of the extracellular domain of RPTP-B (which is commonly retained in RPTP-A, a long form of RPTP) play a crucial role in its interaction with VacA, resulting in vacuolation as well as Git-1 phosphorylation. Transfected cells expressing deletion mutant 752, which lacks QTTQP, or the double point mutant 747 (T748A,T749A) had diminished vacuolation in response to VacA. Treatment of RPTP-B and 747 (which have QTTQP at 747–751) with neuraminidase and O-glycosidase diminished their VacA binding, whereas chondroitinase ABC did not have an effect. No inhibitory effect of pleiotrophin, a natural RPTP ligand, on VacA binding to RPTP-B or 747 was observed, supporting the conclusion that the extracellular region of RPTP-B responsible for VacA binding is different from that involved in binding pleiotrophin. These data define the region in the RPTP extracellular domain critical for VacA binding, in particular the sequence QTTQP at positions 747–751 with crucial threonines at positions 748 and 749 and are consistent with a role for terminal sialic acids possibly because of threonine glycosylation.

Received for publication, June 10, 2004 , and in revised form, September 13, 2004.

^* This work was supported by grants-in-aid for scientific research from the Ministry of Education, Science, and Culture of Japan. 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: Dept. of Bacteriology, Institute of Tropical Medicine, Nagasaki University, Nagasaki 8528523, Japan. Tel.: 81-95-849-7831; Fax: 81-95-849-7805; E-mail: hirayama{at}net.nagasaki-u.ac.jp.

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