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Induction of protein tyrosine phosphorylation in human natural killer cells
by triggering via alpha 4 beta 1 or alpha 5 beta 1 integrins
H Rabinowich, WC Lin, M Manciulea, RB Herberman and TL Whiteside
Department of Pathology, University of Pittsburgh School of Medicine, PA,
USA.
Recent studies have shown that cell-surface integrins expressed on
platelets, fibroblasts, or carcinoma cell lines serve not only as adhesion
receptors that connect the extracellular matrix to the cytoskeleton, but
also as signal-transducing molecules involved in altering cellular patterns
of tyrosine phosphorylation. In this present report we provide evidence
that adhesion of freshly purified human natural killer (NK) cells to
fibronectin (FN) induces tyrosine phosphorylation of intracellular proteins
of approximate molecular mass of 60, 70, and 120 kD. Increases in
phosphorylation induced by NK cell binding to immobilized FN were partially
blocked by EILDV- (CS-1) or RGD-containing peptides, which compete
specifically for a distinct binding site for either alpha 4 beta 1 or alpha
5 beta 1 integrins, respectively, within the FN molecule. The presence of
either one of the inhibitory peptides alone inhibited tyrosine
phosphorylation primarily during short-term (30 minutes) and, to a lesser
extent, during long- term (2 to 3 hours) periods of adhesion. These
observations indicate that triggering either via alpha 4 beta 1 or alpha 5
beta 1 integrins, which are constitutively expressed on NK cells, induces
protein tyrosine phosphorylation. Moreover, FN fragments of 40 or 120 kD,
known to contain the binding sites for alpha 4 beta 1 or alpha 5 beta 1
integrins, respectively, used as immobilized substrates for NK cell
adhesion, were able to initiate tyrosine kinase activity. The induced
tyrosine phosphorylation was observed mainly on intracellular proteins of
greater than 50 kD molecular weight. We have identified a 70-kD tyrosine
phosphoprotein as paxillin, a cytoskeletal-associated tyrosine kinase
substrate previously identified in fibroblasts and shown to localize to
focal adhesions. Thus, interaction of NK cells with immobilized
extracellular matrix glycoproteins required for migration and extravasation
of these cells involves activation of intracellular protein tyrosine
kinases and tyrosine phosphorylation of cytoskeleton- associated protein,
paxillin, which may play a role in signaling between beta 1 integrins and
the underlying cytoskeleton.
Volume 85,
Issue 7,
pp. 1858-1864,
04/01/1995
Copyright © 1995 by The American Society of Hematology
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