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J. Biol. Chem., Vol. 279, Issue 28, 29450-29460, July 9, 2004

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Positive Regulation of Phagocytosis by SIRP and Its Signaling Mechanism in Macrophages^*

Akiko Hayashi, Hiroshi Ohnishi, Hideki Okazawa, Seshiru Nakazawa, Hiroshi Ikeda, Sei-ichiro Motegi, Naoko Aoki¶, Shoji Kimura||, Masahiko Mikuni, 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 Department of Psychiatry and Human Behavior, Gunma University Graduate School of Medicine, 3-39-22 Showa-Machi, Maebashi, Gunma 371-8511, and the ^¶Department of Pathology and ^||School of Nursing, Asahikawa Medical College, Higashi 2-1-1, Midorigaoka, Asahikawa 078-8510, Japan

SIRP (signal-regulatory protein ) is a transmembrane protein that is expressed in hematopoietic cells but whose functions are unknown. We have now cloned mouse SIRP cDNA and have shown that the gene is expressed in various tissues in addition to cells of the macrophage lineage. Engagement of SIRP by specific monoclonal antibodies promoted Fc receptor-dependent or -independent phagocytosis in mouse peritoneal macrophages. It also induced marked activation of MAPK and the upstream kinase MEK but weak activation of Akt. MEK inhibitors markedly blocked the promotion of phagocytosis by SIRP, whereas an inhibitor of phosphoinositide 3-kinase partly blocked such response. In addition, inhibitors of myosin light chain kinase or of myosin ATPase blocked the promotion of phagocytosis by SIRP. Furthermore, SIRP induced the formation of filopodia and lamellipodia in macrophages as well as the translocation of activated MAPK to these structures. It also elicited tyrosine phosphorylation of DAP12, Syk, and SLP-76, and a Syk inhibitor blocked the promotion of phagocytosis and activation of MAPK by SIRP. Our results suggest that engagement of SIRP promotes phagocytosis in macrophages by inducing the tyrosine phosphorylation of DAP12, Syk, and SLP-76 and the subsequent activation of a MEK-MAPK-myosin light chain kinase cascade.

Received for publication, January 28, 2004 , and in revised form, April 27, 2004.

The nucleotide sequence(s) reported in this paper has been submitted to the DDBJ/GenBank^TM/EBI Data Bank with accession number(s) AB112022, AB112023, AB112024, and AB112025.

^* This work was supported by a grant-in-aid for scientific research on priority areas cancer, a grant-in-aid for scientific research (B), a 21st Century COE program grant from the Ministry of Education, Culture, Sports, Science, and Technology of Japan, a grant from the Uehara Memorial Foundation, a grant from the Brain Science Foundation, a grant from the Nakajima Foundation, and a grant from the Japan Research Foundation for Clinical Pharmacology. 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: Biosignal Research Center, Institute for Molecular and Cellular Regulation, Gunma University, 3-39-15 Showa-Machi, Maebashi, Gunma 371-8512, Japan. Tel.: 81-27-220-8865; Fax: 81-27-220-8897; E-mail: matozaki{at}showa.gunma-u.ac.jp.

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