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J. Biol. Chem., Vol. 278, Issue 37, 34854-34863, September 12, 2003

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Interaction of SAP-1, a Transmembrane-type Protein-tyrosine Phosphatase, with the Tyrosine Kinase Lck

ROLES IN REGULATION OF T CELL FUNCTION^*

Tomokazu Ito , Hideki Okazawa , Koji Maruyama , Kyoko Tomizawa , Sei-ichiro Motegi , Hiroshi Ohnishi , Hiroyuki Kuwano ¶, Atsushi Kosugi  and Takashi Matozaki  ||

From the Biosignal Research Center, Institute for Molecular and Cellular Regulation, Gunma University, 3-39-15 Showa-Machi, Maebashi, Gunma 371-8512, the School of Allied Health Sciences, Faculty of Medicine, Osaka University, 1-7 Yamada-oka, Suita, Osaka 565-0871, and the ^¶Department of General Surgical Science (Surgery I), Gunma University Graduate School of Medicine, 3-39-22 Showa-Machi, Maebashi 371-8511, Japan

SAP-1 is a transmembrane-type protein-tyrosine phosphatase that is expressed in most tissues but whose physiological functions remain unknown. The cytoplasmic region of SAP-1 has now been shown to bind directly the tyrosine kinase Lck. Overexpression of wild-type SAP-1, but not that of a catalytically inactive mutant of SAP-1, inhibited both the basal and the T cell antigen receptor (TCR)-stimulated activity of Lck in human Jurkat T cell lines. Lck served as a direct substrate for dephosphorylation by SAP-1 in vitro. Overexpression of wild-type SAP-1 in Jurkat cells also: (i) inhibited both the activation of mitogen-activated protein kinase and the increase in cell surface expression of CD69 induced by TCR stimulation; (ii) reduced the extent of the TCR-induced increase in the tyrosine phosphorylation of ZAP-70 or that of LAT; (iii) reduced both the basal level of tyrosine phosphorylation of p62^dok, as well as the increase in the phosphorylation of this protein induced by CD2 stimulation; and (iv) inhibited cell migration. These results thus suggest that the direct interaction of SAP-1 with Lck results in inhibition of the kinase activity of the latter and a consequent negative regulation of T cell function.

Received for publication, January 21, 2003 , and in revised form, June 25, 2003.

^* This work was supported by a grant-in-aid for scientific research on priority areas (cancer), a grant-in-aid for scientific research (B), and a grant-in-aid for the 21st Century COE Program from the Ministry of Education, Culture, Sports, Science, and Technology of Japan; a grant from the Yamanouchi Foundation for Research on Metabolic Disorders; a grant from the Novartis Foundation (Japan) for the Promotion of Science; a grant from ONO Medical Research Foundation; a grant from the Cosmetology Research Foundation; a grant from Mitsui Life Social Welfare Foundation; and a grant from the Public Trust Haraguchi Memorial Cancer Research Fund. 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. Tel.: 81-27-220-8865; Fax: 81-27-220-8897; E-mail: matozaki{at}showa.gunma-u.ac.jp.

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