Positive Regulation of Phagocytosis by SIRPβ and Its Signaling Mechanism in Macrophages

• Published in: The Journal of biological chemistry Vol. 279; no. 28; pp. 29450 - 29460
• Main Authors: Hayashi, Akiko, Ohnishi, Hiroshi, Okazawa, Hideki, Nakazawa, Seshiru, Ikeda, Hiroshi, Motegi, Sei-ichiro, Aoki, Naoko, Kimura, Shoji, Mikuni, Masahiko, Matozaki, Takashi
• Format: Journal Article
• Language: English
• Published: 09.07.2004
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M400950200

SIRP beta (signal-regulatory protein beta ) is a transmembrane protein that is expressed in hematopoietic cells but whose functions are unknown. We have now cloned mouse SIRP beta cDNA and have shown that the gene is expressed in various tissues in addition to cells of the macrophage lineage. Engagement of SIRP beta by specific monoclonal antibodies promoted Fc gamma 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 beta , 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 beta . Furthermore, SIRP beta 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 beta . Our results suggest that engagement of SIRP beta 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.