The Journal of Experimental Medicine
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J. Exp. Med.
© The Rockefeller University Press
0022-1007/97/10/1027/13 $2.00
Volume 186, Number 7, October 6, 1997 1027-1039

A Critical Role for Syk in Signal Transduction and Phagocytosis Mediated by Fcgamma Receptors on Macrophages

By Mary T. Crowley,* Patrick S. Costello,§ Cheryl J. Fitzer-Attas,* Martin Turner,§ Fanying Meng,Dagger Clifford Lowell,Dagger Victor L. J. Tybulewicz,§ and Anthony L. DeFranco*

From the G.W. Hooper Foundation, * Department of Microbiology and Immunology, and Dagger  Department of Laboratory Medicine, University of California, San Francisco, California 94143-0552; and the § National Institute for Medical Research, London NW7 1AA, United Kingdom

Receptors on macrophages for the Fc region of IgG (Fcgamma R) mediate a number of responses important for host immunity. Signaling events necessary for these responses are likely initiated by the activation of Src-family and Syk-family tyrosine kinases after Fcgamma R cross-linking. Macrophages derived from Syk-deficient (Syk-) mice were defective in phagocytosis of particles bound by Fcgamma Rs, as well as in many Fcgamma R-induced signaling events, including tyrosine phosphorylation of a number of cellular substrates and activation of MAP kinases. In contrast, Syk- macrophages exhibited normal responses to another potent macrophage stimulus, lipopolysaccharide. Phagocytosis of latex beads and Escherichia coli bacteria was also not affected. Syk- macrophages exhibited formation of polymerized actin structures opposing particles bound to the cells by Fcgamma Rs (actin cups), but failed to proceed to internalization. Interestingly, inhibitors of phosphatidylinositol 3-kinase also blocked Fcgamma R-mediated phagocytosis at this stage. Thus, PI 3-kinase may participate in a Syk-dependent signaling pathway critical for Fcgamma R-mediated phagocytosis. Macrophages derived from mice deficient for the three members of the Src-family of kinases expressed in these cells, Hck, Fgr, and Lyn, exhibited poor Syk activation upon Fcgamma R engagement, accompanied by a delay in Fcgamma R-mediated phagocytosis. These observations demonstrate that Syk is critical for Fcgamma R-mediated phagocytosis, as well as for signal transduction in macrophages. Additionally, our findings provide evidence to support a model of sequential tyrosine kinase activation by Fcgamma R's analogous to models of signaling by the B and T cell antigen receptors.


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