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Blood, 1 September 2002, Vol. 100, No. 5, pp. 1852-1859
PHAGOCYTES
SHP-1 regulates Fc receptor-mediated phagocytosis and the
activation of RAC
Anita M. Kant,
Pradip De,
Xiaodong Peng,
Taolin Yi,
David J. Rawlings,
Jong Suk Kim, and
Donald L. Durden
From the Herman B. Wells Center for Pediatrics
Research, Department of Pediatrics, Biochemistry and Molecular Biology,
Indiana University School of Medicine, Indianapolis; the Childrens
Hospital Los Angeles Research Institute, University of Southern
California School of Medicine, Los Angeles; the Department of
Pediatrics, Division of Immunology/Rheumatology, University of
Washington School of Medicine, Seattle; and the Department of Cancer
Biology, Cleveland Clinic Foundation Research Institute, OH.
Fc receptor-mediated phagocytosis is a complex process
involving the activation of protein tyrosine kinases, events that are
potentially down-regulated by protein tyrosine phosphatases. We used
the J774A.1 macrophage cell line to examine the roles played by the
protein tyrosine phosphatase SHP-1 in the negative regulation of Fc
receptor-mediated phagocytosis. Stimulation with sensitized sheep red
blood cells (sRBCs) induced tyrosine phosphorylation of CBL and
association of CBL with CRKL. These events were completely or partially
abrogated by PP1 or the heterologous expression of dominant-negative
SYK, respectively. Heterologous expression of wild-type but not
catalytically inactive SHP-1 also completely abrogated the phagocytosis
of IgG-sensitized sRBCs. Most notably, overexpressed SHP-1 associates
with CBL and this association led to CBL dephosphorylation, loss of the
CBL-CRKL interaction, and the suppression of Rac activation. These data represent the first direct evidence that SHP-1 is involved in the
regulation of Fc receptor-mediated phagocytosis and suggest that
activating signals mediated by SRC family kinases SYK, CBL, phosphatidyl inositol-3 (PI-3) kinase, and Rac are directly opposed by
inhibitory signals through SHP-1.

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