The protein tyrosine phosphatase SHP-1 regulates integrin-mediated adhesion of macrophages.
The Src homology 2 domain phosphatase-1 (SHP-1) is a tyrosine phosphatase containing two amino-terminal SH2 domains and is expressed primarily by hematopoietic-derived cells [1]. The viable motheaten (Hcphme-v) mutant mice (mev) suffer from progressive inflammation due to a deficiency of SHP-1 enzyme activity [2,3] and die at 3-4 months of age from macrophage and neutrophil accumulation in the lung [4]. The mechanism by which SHP-1 deficiency leads to inflammation is unknown. We found that macrophages from mev mice adhered and spread to a greater extent than normal macrophages through alpha m beta 2 integrin-mediated contacts. Whereas macrophages deficient in the transmembrane tyrosine phosphatase CD45 (CD45-/-) spontaneously detached from alpha m beta 2 integrin contacts [5], cells deficient in both CD45 and SHP-1 did not. In SHP-1 deficient macrophages there was a 10-15-fold increase in D-3 phospholipid products of phosphatidylinositol (PI) 3-kinase. Concomitantly, there was a 2-5-fold increase in membrane-associated PI 3-kinase activity in mev macrophages relative to normal macrophages. Treatment of macrophages with the PI 3-kinase inhibitors wortmannin or LY294002 resulted in a dramatic detachment of cells, indicating that PI 3-kinase activity is required for adhesion. These data demonstrate that SHP-1 is necessary for detachment from alpha m beta 2 integrin-mediated contacts in primary macrophages and suggest that a defect in this pathway may contribute to inflammatory disease.
Roach
T I
TI
Department of Pathology, Howard Hughes Medical Institute, Washington University School of Medicine, St Louis, Missouri 63130, USA.
Slater
S E
SE
White
L S
LS
Zhang
X
X
Majerus
P W
PW
Brown
E J
EJ
Thomas
M L
ML
D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology; D002448:Cell Adhesion / Q000502:physiology*; D007249:Inflammation / Q000235:genetics / Q000503:physiopathology; D016023:Integrins / Q000502:physiology*; D047908:Intracellular Signaling Peptides and Proteins; D017493:Leukocyte Common Antigens / Q000235:genetics / Q000502:physiology*; D008264:Macrophages / Q000166:cytology / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; 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 / Q000378:metabolism*; D054593:SH2 Domain-Containing Protein Tyrosine Phosphatases; D018909:src Homology Domains
D016023:Integrins; D047908:Intracellular Signaling Peptides and Proteins; D019869:Phosphatidylinositol 3-Kinases; D054645:Protein Phosphatase 1; D017493:Leukocyte Common Antigens; 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