Regulation of the very late antigen-4-mediated adhesive activity of normal and nonreleaser basophils: roles for Src, Syk, and phosphatidylinositol 3-kinase.
Normal human basophils express the integrin, VLA-4, and cross-linking their high-affinity IgE receptor, FcepsilonRI, increases their VLA-4-dependent adhesion to VCAM-1-transfected Chinese hamster ovary (CHO) cells. Here we show that the FcepsilonRI-mediated up-regulation of normal basophil VLA-4 adhesion is abolished by the Src inhibitor, PP1, the Syk inhibitor, ER-27319, and the phosphatidylinositol 3-kinase inhibitor, wortmannin. PP1, but not ER-27319 or wortmannin, also reduces basal adhesion and adhesion stimulated by chemotactic peptide, by Ca(++) ionophores, and by phorbol myristate acetate (PMA). Nonreleaser basophils (the consistently Syk-deficient, variably Lyn-deficient, severely degranulation-impaired cells found in about 10% of donors) share the PP1 phenotype of lowered basal adhesion, no FcepsilonRI-mediated adhesion up-regulation, and reduced adhesive responses to chemoattractant ionophores and PMA. These results implicate Src kinases in the control of basal VLA-4 activity and place Syk and phosphatidylinositol 3-kinase in the pathway linking FcepsilonRI cross-linking to VLA-4 up-regulation. Both Src and Syk-regulated components of adhesion may be impaired in nonreleaser basophils.
Andrews
R P
RP
Department of Pathology, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA. randrews@salud.unm.edu
Kepley
C L
CL
Youssef
L
L
Wilson
B S
BS
Oliver
J M
JM
D000166:Acridines / Q000494:pharmacology; D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D001491:Basophils / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology; D016466:CHO Cells; D000001:Calcimycin / Q000494:pharmacology; D002118:Calcium / Q000494:pharmacology; D002448:Cell Adhesion / Q000187:drug effects; D006224:Cricetinae; D003412:Cricetulus; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004792:Enzyme Precursors / Q000037:antagonists & inhibitors / Q000502:physiology*; D006801:Humans; D007152:Immunologic Capping; D039041:Integrin alpha4beta1; D016023:Integrins / Q000502:physiology*; D047908:Intracellular Signaling Peptides and Proteins; D007476:Ionophores / Q000494:pharmacology; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*; D011720:Pyrazoles / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D017455:Receptors, IgE / Q000502:physiology; D016201:Receptors, Lymphocyte Homing / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D000072377:Syk Kinase; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014162:Transfection; D015854:Up-Regulation; D019010:Vascular Cell Adhesion Molecule-1 / Q000235:genetics / Q000502:physiology; D000077191:Wortmannin; D019061:src-Family Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*
D000166:Acridines; D000730:Androstadienes; D000001:Calcimycin; D002118:Calcium; D004791:Enzyme Inhibitors; D004792:Enzyme Precursors; D039041:Integrin alpha4beta1; D016023:Integrins; D047908:Intracellular Signaling Peptides and Proteins; D007476:Ionophores; D009240:N-Formylmethionine Leucyl-Phenylalanine; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011505:Protein-Tyrosine Kinases; D011720:Pyrazoles; D011743:Pyrimidines; D017455:Receptors, IgE; D016201:Receptors, Lymphocyte Homing; D011993:Recombinant Fusion Proteins; D000072377:Syk Kinase; D013755:Tetradecanoylphorbol Acetate; D019010:Vascular Cell Adhesion Molecule-1; D000077191:Wortmannin; D019061:src-Family Kinases; C108123:4-amino-5-(4-methylphenyl)-7-(tert-butyl)pyrazolo(3,4-d)pyrimidine; C109226:ER 27319; C000606896:SYK protein, human