Phosphoinositide 3-kinase modulation of beta(3)-integrin represents an endogenous "braking" mechanism during neutrophil transmatrix migration.
During episodes of inflammation, neutrophils (polymorphonuclear leukocytes [PMNs]) encounter subendothelial matrix substrates that may require additional signaling pathways as directives for movement through the extracellular space. Using an in vitro endothelial and epithelial model, inhibitors of phosphoinositide 3-kinase (PI3K) were observed to promote chemoattractant-stimulated migration by as much as 8 +/- 0.3-fold. Subsequent studies indicated that PMNs respond in a similar manner to RGD-containing matrix substrates and that PMN-matrix interactions are potently inhibited by antibodies directed against beta(3)- but not beta(1)-integrin antibodies, and that PI3K inhibitors block beta(3)-integrin dependence. Biochemical analysis of intracellular beta(3)-integrin uncoupling by PI3K inhibitors revealed diminished beta(3)-integrin tyrosine phosphorylation and decreased association with p72(syk). Similarly, the p72(syk) inhibitor piceatannol promoted PMN transmatrix migration, whereas HIV-tat peptide-facilitated loading of peptides corresponding to the beta(3)-integrin cytoplasmic tail identified the functional tyrosine residues for this activity. These data indicate that PI3K-regulated beta(3)-integrin represents a natural "braking" mechanism for PMNs during transit through the extracellular matrix.
Bruyninckx
W J
WJ
Center for Experimental Therapeutics and Reperfusion Injury, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
Comerford
K M
KM
Lawrence
D W
DW
Colgan
S P
SP
D000730:Androstadienes / Q000494:pharmacology; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D015703:Antigens, CD / Q000737:chemistry / Q000276:immunology / Q000502:physiology*; D002460:Cell Line; D002634:Chemotaxis, Leukocyte; D003593:Cytoplasm / Q000737:chemistry; D004730:Endothelium, Vascular / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004792:Enzyme Precursors / Q000037:antagonists & inhibitors / Q000502:physiology; D004848:Epithelium / Q000502:physiology; D005109:Extracellular Matrix / Q000502:physiology*; D006801:Humans; D039661:Integrin beta3; D047908:Intracellular Signaling Peptides and Proteins; D007975:Leukotriene B4 / Q000494:pharmacology; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology; D009504:Neutrophils / Q000502:physiology*; D009195:Peroxidase / Q000032:analysis; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D019000:Phosphotyrosine / Q000378:metabolism; D010980:Platelet Membrane Glycoproteins / Q000737:chemistry / Q000276:immunology / Q000502:physiology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000502:physiology; D000072377:Syk Kinase; D000077191:Wortmannin
D000730:Androstadienes; D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D004791:Enzyme Inhibitors; D004792:Enzyme Precursors; D039661:Integrin beta3; D047908:Intracellular Signaling Peptides and Proteins; D007975:Leukotriene B4; D009240:N-Formylmethionine Leucyl-Phenylalanine; D009195:Peroxidase; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D019000:Phosphotyrosine; D010980:Platelet Membrane Glycoproteins; D011505:Protein-Tyrosine Kinases; D000072377:Syk Kinase; D000077191:Wortmannin; C000606896:SYK protein, human