Deficiency of   Src homology 2-containing phosphatase 1 results in abnormalities in murine neutrophil function: studies in motheaten mice.
Neutrophils, an essential component of the innate immune system, are regulated in part by signaling pathways involving protein tyrosine phosphorylation. While protein tyrosine kinase functions in regulating neutrophil behavior have been extensively investigated, little is known about the role for specific protein tyrosine phosphatases (PTP) in modulating neutrophil signaling cascades. A key role for Src homology 2 domain-containing phosphatase 1 (SHP-1), a PTP, in neutrophil physiology is, however, implied by the overexpansion and inappropriate activation of granulocyte populations in SHP-1-deficient motheaten (me/me) and motheaten viable (me(v)/me(v)) mice. To directly investigate the importance of SHP-1 to phagocytic cell function, bone marrow neutrophils were isolated from both me/me and me(v)/me(v) mice and examined with respect to their responses to various stimuli. The results of these studies revealed that both quiescent and activated neutrophils from motheaten mice manifested enhanced tyrosine phosphorylation of cellular proteins in the 60- to 80-kDa range relative to that detected in wild-type congenic control neutrophils. MOTHEATEN: neutrophils also demonstrated increased oxidant production, surface expression of CD18, and adhesion to protein-coated plastic. Chemotaxis, however, was severely diminished in the SHP-deficient neutrophils relative to control neutrophils, which was possibly attributable to a combination of defective deadhesion and altered actin assembly. Taken together, these results indicate a significant role for SHP-1 in modulating the tyrosine phosphorylation-dependent signaling pathways that regulate neutrophil microbicidal functions.
Kruger
J
J
Division of Respirology, The Toronto General Hospital Research Institute of the University Health Network, Toronto, Ontario, Canada.
Butler
J R
JR
Cherapanov
V
V
Dong
Q
Q
Ginzberg
H
H
Govindarajan
A
A
Grinstein
S
S
Siminovitch
K A
KA
Downey
G P
GP
D000818:Animals; D001854:Bone Marrow Cells / Q000201:enzymology; D018821:CD18 Antigens / Q000096:biosynthesis; D002448:Cell Adhesion / Q000235:genetics / Q000276:immunology; D002462:Cell Membrane / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D002469:Cell Separation; D048429:Cell Size / Q000235:genetics / Q000276:immunology; D002634:Chemotaxis, Leukocyte / Q000235:genetics / Q000276:immunology; D003599:Cytoskeleton / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D022423:Myeloid Cells / Q000201:enzymology; D009504:Neutrophils / Q000201:enzymology* / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D016877:Oxidants / Q000096:biosynthesis; D010587:Phagocytosis / Q000235:genetics; D054645:Protein Phosphatase 1; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases / Q000172:deficiency* / Q000235:genetics*; D054593:SH2 Domain-Containing Protein Tyrosine Phosphatases; D018909:src Homology Domains / Q000235:genetics* / Q000276:immunology*
D018821:CD18 Antigens; D047908:Intracellular Signaling Peptides and Proteins; D016877:Oxidants; D054645:Protein Phosphatase 1; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases; C516725:Ptpn11 protein, mouse; C509248:Ptpn6 protein, mouse; D054593:SH2 Domain-Containing Protein Tyrosine Phosphatases