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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
Fc
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 Fc
receptor (Fc
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 Fc
R engagement but responded
normally to tetradecanoyl phorbol acetate stimulation. Syk-deficient
macrophages were defective in phagocytosis induced by Fc
R but showed
normal phagocytosis in response to complement. The tyrosine
phosphorylation of multiple cellular polypeptides, including the Fc
R
chain, as well as Erk2 activation, was compromised in
Syk
/
macrophages after Fc
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 Fc
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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