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J. Biol. Chem., Vol. 283, Issue 3, 1653-1659, January 18, 2008

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Novel Binding Site for Src Homology 2-containing Protein-tyrosine Phosphatase-1 in CD22 Activated by B Lymphocyte Stimulation with Antigen^*

Chenghua Zhu^¶, Motohiko Sato, Teruhiko Yanagisawa, Manabu Fujimoto^||, Takahiro Adachi^¶, and Takeshi Tsubata^¶1

From the Laboratory of Immunology, School of Biomedical Science, and the Department of Immunology, Medical Research Institute, Tokyo Medical and Dental University, Tokyo 113-8510, Japan, the ^||Department of Dermatology, Kanazawa University Graduate School of Medical Science, Kanazawa, Ishikawa 920-8641, Japan, and ^¶Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, Tokyo 113-8510, Japan

CD22, a B lymphocyte membrane glycoprotein, contains immunoreceptor tyrosine-based inhibition motifs (ITIMs) in the cytoplasmic region and recruits Src homology 2-containing protein-tyrosine phosphatase-1 (SHP-1) to the phosphorylated ITIMs upon ligation of B lymphocyte antigen receptor (BCR), thereby negatively regulating BCR signaling. Among the three previously identified ITIMs, both ITIMs containing tyrosine residues at position 843 (Tyr⁸⁴³) and 863 (Tyr⁸⁶³), respectively, are shown to be required for CD22 to recruit SHP-1 and regulate BCR signaling upon BCR ligation by anti-Ig antibody (Ab), indicating that CD22 has the SHP-1-binding domain at the region containing Tyr⁸⁴³ and Tyr⁸⁶³. Here we address the requirement of CD22 for SHP-1 recruitment and BCR regulation upon BCR ligation by antigen, which induces much stronger CD22 phosphorylation than anti-Ig Ab does. We demonstrate that the CD22 mutant in which both Tyr⁸⁴³ and Tyr⁸⁶³ are replaced by phenylalanine (CD22F5/6) recruits SHP-1 and regulates BCR signaling upon stimulation with antigen but not anti-Ig Ab. This result strongly suggests that CD22 contains another SHP-1 binding domain that is specifically activated upon stimulation with antigen. Both of the flanking sequences of Tyr⁷⁸³ and Tyr⁸¹⁷ fit the consensus sequence of ITIM, and the CD22F5/6 mutant requires these tyrosine residues for SHP-1 binding and BCR regulation. Thus, these ITIMs constitute a novel conditional SHP-1-binding site of CD22 that is activated upon BCR ligation by antigen but not by anti-Ig Ab.

Received for publication, August 8, 2007 , and in revised form, October 1, 2007.

^* This work was supported by grants from the Ministry of Education, Culture, Sports, Science, and Technology and from the Japan Society for the Promotion of Science. 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Table S1 and Figs. S1 and S2.

¹ To whom correspondence should be addressed: Laboratory of Immunology, School of Biomedical Science, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan. Tel.: 81-3-5803-5817; Fax: 81-3-5684-0717; E-mail: tsubata.imm{at}mri.tmd.ac.jp.

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