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Steven M. Greenberg, M.D.
Associate Professor of Medicine in Pharmacology
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Research
Summary
Macrophage signal transduction; Role of low molecular weight GTPases in innate immunity
The focus of our laboratory is functional aspects of macrophages, particularly phagocytosis. We have utilized several model systems to dissect the signal transduction cascades that underlie phagocytosis by Fc receptors. Fc receptors belong to a family of signal-transducing receptors which share certain common features, including association with immunoreceptor tyrosine activation motif (ITAM)-bearing subunits. In 1993, we established that phagocytosis via Fc receptors is a tyrosine kinase-dependent process. More recently, we have shown that Syk, a cytosolic tyrosine kinase, is a key signaling element from ligated Fc receptors to the cytoskeleton. When clustered autonomously, Syk is capable of transducing a phagocytic signal.
An ongoing project in my laboratory has been exploring mechanisms by which Syk transduces a phagocytic signal. In 1997, we showed that Rac1 and Cdc42, two members of this family, are required for cytoskeletal rearrangements mediated by structurally distinct receptors in macrophages. Together with ARF6, a member of another class of GTPases implicated in both F-actin rearrangements and membrane trafficking, phagocytosis proceeds by activation of an array of GTPases with distinct functions.
More recent studies have centered around innate immune functions of macrophages. Lipopolysaccharide (LPS), a constituent of the cell walls of Gram-negative bacteria, triggers a cascade of phosphorylation events that culminates in expression of proinflammatory cytokines. We have found that the regulation of this cascade of signaling events in macrophages is complex and surprising. Ongoing experiments are being conducted to delineate pathways leading to activation of mitogen- and stress-activated protein kinases.
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Selected Publications:
1. Zhang, Q., Janssen, H., Calafat, J., and Greenberg, S. (1999) ARF6 is required for growth factor- and Rac-mediated membrane ruffling in macrophages at a stage distal to Rac membrane targeting. Mol. Cell. Biol.
19:8158-8168
2. Greenberg, S. (1999) Modular components of phagocytosis. J. Leuk. Biol.
66:712-717
3. Cox, D., Lee, D.J., Dale, B.M., Calafat, J., and Greenberg, S. (2000) A Rab11-containing rapidly recycling compartment in macrophages that promotes phagocytosis. Proc. Natl. Acad. Sci., USA.
97:680-685
4. Cox, D., Dale, B.M., Kashiwada, M., Helgason, C.D., and Greenberg. S. (2001) A regulatory role for SH2 domain-containing inositol 5'-phosphatase (SHIP) in phagocytosis mediated by Fcg receptors and complement receptor 3 ( aMb2; CD11b/CD18). J. Exp. Med
193:61-71
5. Greenberg, S. (2001) Diversity in phagocytic signalling J. Cell Sci
114:1039-1040
6. Grinstein, S. and Greenberg, S. (2001) Update on phagocytosis. Curr. Opin. Immunol.
In press.:
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