SHP-1 regulates Fcgamma receptor-mediated phagocytosis and the activation of RAC.
Fcgamma 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 Fcgamma 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 Fcgamma 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.
Kant
Anita M
AM
Herman B. Wells Center for Pediatrics Research, Indiana University School of Medicine, Indianapolis 46202, USA.
De
Pradip
P
Peng
Xiaodong
X
Yi
Taolin
T
Rawlings
David J
DJ
Kim
Jong Suk
JS
Durden
Donald L
DL
D000818:Animals; D002460:Cell Line; D005786:Gene Expression Regulation / Q000502:physiology; D047908:Intracellular Signaling Peptides and Proteins; D008264:Macrophages / Q000502:physiology; D051379:Mice; D010587:Phagocytosis / Q000502:physiology*; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases / Q000502:physiology*; D017452:Receptors, IgG / Q000502:physiology*; D015398:Signal Transduction; D020744:rac GTP-Binding Proteins / Q000037:antagonists & inhibitors / Q000502:physiology*; D018909:src Homology Domains / Q000502:physiology
D047908:Intracellular Signaling Peptides and Proteins; D017452:Receptors, IgG; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases; C509248:Ptpn6 protein, mouse; D020744:rac GTP-Binding Proteins