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Mol Cell Biol, July 1998, p. 4209-4220, Vol. 18, No. 7
0270-7306/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

The Syk Protein Tyrosine Kinase Is Essential for Fcgamma Receptor Signaling in Macrophages and Neutrophils

Friedemann Kiefer,1 John Brumell,1 2 Nadia Al-Alawi,1 Sylvain Latour,3 Alec Cheng,1 André Veillette,3 Sergio Grinstein,2 and Tony Pawson1 4 *

Programme in Molecular Biology and Cancer, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario M5G 1X5,1 Hospital for Sick Children, Toronto, Ontario M5G 1X8,2 McGill Cancer Centre, McGill University, Montreal, Quebec H3G 1Y6,3 and Department of Molecular and Medical Genetics, University of Toronto, Toronto, Ontario M5S 1A8,4 Canada

Received 24 February 1998/Accepted 20 April 1998

The cytoplasmic protein tyrosine kinase Syk has two amino-terminal SH2 domains that engage phosphorylated immunoreceptor tyrosine-based activation motifs in the signaling subunits of immunoreceptors. Syk, in conjunction with Src family kinases, has been implicated in immunoreceptor signaling in both lymphoid and myeloid cells. We have investigated the role of Syk in Fcgamma receptor (Fcgamma R)-dependent and -independent responses in bone marrow-derived macrophages and neutrophils by using mouse radiation chimeras reconstituted with fetal liver cells from Syk-/- embryos. Chimeric mice developed an abdominal hemorrhage starting 2 to 3 months after transplantation that was ultimately lethal. Syk-deficient neutrophils derived from the bone marrow were incapable of generating reactive oxygen intermediates in response to Fcgamma R engagement but responded normally to tetradecanoyl phorbol acetate stimulation. Syk-deficient macrophages were defective in phagocytosis induced by Fcgamma R but showed normal phagocytosis in response to complement. The tyrosine phosphorylation of multiple cellular polypeptides, including the Fcgamma R gamma  chain, as well as Erk2 activation, was compromised in Syk-/- macrophages after Fcgamma R stimulation. In contrast, the induction of nitric oxide synthase in macrophages stimulated with lipopolysaccharide and gamma interferon was not dependent on Syk. Surprisingly, Syk-deficient macrophages were impaired in the ability to survive or proliferate on plastic petri dishes. Taken together, these results suggest that Syk has specific physiological roles in signaling from Fcgamma Rs in neutrophils and macrophages and raise the possibility that in vivo, Syk is involved in signaling events other than those mediated by immunoreceptors.

* Corresponding author. Mailing address: Samuel Lunenfeld Research Institute, Mount Sinai Hospital, 600 University Avenue, Toronto, Ontario M5G 1X5, Canada. Phone: (416) 586-8262. Fax: (416) 586-8857. E-mail: Pawson{at}mshri.on.ca.

Mol Cell Biol, July 1998, p. 4209-4220, Vol. 18, No. 7
0270-7306/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.


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