Regulation of alpha 4 integrin avidity in human B cells: requirement for dephosphorylation events for high avidity VCAM-1 binding.
The authors compared the phosphorylation-dependent signal transduction pathways involved in the regulation of adhesiveness of integrin LFA-1 with that of alpha 4 integrins binding to VCAM-1. The authors developed an in vitro method to monitor changes in adhesiveness using a VCAM-1 fusion protein coupled to magnetic beads. For LFA-1, a similar method has previously been established using an ICAM-1 fusion protein. Binding of cells was monitored and found to be strictly integrin alpha 4 and VCAM-1 dependent. The serine/threonine phosphatase inhibitors okadaic acid and calyculin A were equally potent in inhibiting binding to VCAM-1 as to ICAM-1, and inhibition of protein phosphatase-1 (PP1) is proposed to be the important denominator. Similarly, the phorbol ester PDBu, potentially stimulating protein phosphatase-1 and staurosporine, an inhibitor of serine/threonine kinases, enhanced adhesion to VCAM-1 as has previously been shown for ICAM-1. A major difference was that a significant portion of the binding to VCAM-1 was not susceptible to inhibition by drugs while binding to ICAM-1 could be completely inhibited. We propose that the adhesiveness of the alpha 4 integrins for VCAM-1 and of LFA-1 for ICAM-1 is regulated by similar or identical protein kinases and phosphatases.
Hedman
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H
Department of Cell and Molecular Biology, University of Umeå, Sweden.
Lundgren
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E
D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology*; D002448:Cell Adhesion / Q000187:drug effects; D002460:Cell Line; D004988:Ethers, Cyclic / Q000494:pharmacology; D006801:Humans; D039041:Integrin alpha4beta1; D016023:Integrins / Q000378:metabolism*; D008387:Marine Toxins; D019319:Okadaic Acid; D010080:Oxazoles / Q000494:pharmacology; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors; D010766:Phosphorylation; D054645:Protein Phosphatase 1; D016201:Receptors, Lymphocyte Homing / Q000378:metabolism*; D015398:Signal Transduction; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism*
D004988:Ethers, Cyclic; D039041:Integrin alpha4beta1; D016023:Integrins; D008387:Marine Toxins; D010080:Oxazoles; D016201:Receptors, Lymphocyte Homing; D019010:Vascular Cell Adhesion Molecule-1; C071777:integrin alpha4beta7; D019319:Okadaic Acid; C059041:calyculin A; D010749:Phosphoprotein Phosphatases; D054645:Protein Phosphatase 1