The Journal of Experimental Medicine
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© The Rockefeller University Press, 0022-1007/2000/2/515/ $5.00
The Journal of Experimental Medicine, Volume 191, Number 3, February 7, 2000 515-528

Original Article

Negative Regulation of Phagocytosis in Murine Macrophages by the Src Kinase Family Member, Fgr

Hattie D. Greshama,b, Benjamin M. Dalea,b, Jeffrey W. Potterc, Peter W. Changc, Charlotte M. Vinesc, Clifford A. Lowelld, Carl F. Lagenaure, and Cheryl L. Willmanc
a From the Research Service, Albuquerque Veterans Administration Medical Center, Albuquerque, New Mexico 87108
b Department of Molecular Genetics and Microbiology, University of New Mexico, Albuquerque, New Mexico 87131
c Department of Pathology, University of New Mexico, Albuquerque, New Mexico 87131
d Department of Laboratory Medicine, University of California, San Francisco, San Francisco, California 94143
e Department of Neurobiology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213

Correspondence to: Hattie D. Gresham, Department of Molecular Genetics and Microbiology, Rm. 379, BMSB, 915 Camino de Salud, University of New Mexico, Albuquerque, NM 87131-5276. Tel:505-272-5764 Fax:505-272-6029 E-mail:hgresham{at}salud.unm.edu.

Ingestion of opsonized pathogens by professional phagocytes results in the generation and release of microbicidal products that are essential for normal host defense. Because these products can result in significant tissue injury, phagocytosis must be regulated to limit damage to the host while allowing for optimal clearance and destruction of opsonized pathogens. To pursue negative regulation of phagocytosis, we assessed the effect of the Src kinase family member, Fgr, on opsonin-dependent phagocytosis by mouse macrophages. We chose Fgr because it is present in high concentrations in circulating phagocytes but is not essential for Fc{gamma} receptor–mediated ingestion by mouse macrophages. Although expression of Fgr both in a macrophage cell line and in primary macrophages significantly attenuates ingestion mediated by Fc{gamma} receptors and CR3, it does not affect macropinocytosis or receptor-mediated endocytosis. This selective effect of Fgr is independent of its tyrosine kinase function. After Fc{gamma} receptor cross-linking, Fgr becomes associated with the immunoreceptor tyrosine-based inhibition motif (ITIM)–containing receptor, SIRP{alpha} (a member of the signal-regulatory protein family, also known as Src homology 2 domain–containing protein tyrosine phosphatase [SHP] substrate 1 [SHPS-1], brain immunoglobulin-like molecule with tyrosine-based activation motifs [BIT], and P84) and potentiates the association of the phosphatase SHP-1 with SIRP{alpha}. This association is responsible, at least in part, for decreasing positive signaling essential for optimal phagocytosis. These data demonstrate an important negative regulatory role for this Src kinase family member and suggest that this homeostatic function must be overcome for optimal uptake and clearance of opsonized pathogens.

Key Words: phagocytes, Src family kinases, protein tyrosine phosphatase


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