Urokinase-type plasminogen activator receptor crosslinking in an NK cell line increases integrin surface expression by the MAP kinase/ERK 1/2 signaling pathway.
Urokinase-type plasminogen activator receptor (uPAR) is attached to cell membranes by a glycosylphosphatidylinositol (GPI) anchor, and as such is devoid of an intracellular domain, but is nevertheless able to initiate signal transduction. Herein, we report a relationship between integrins and uPAR on the surface of the human NK cell line, YT. Our data reveals that crosslinking uPAR, which mimics uPAR clustering at focal adhesion sites, causes increases in expression of the alpha(M), alpha(V), and beta(2) integrins on the surface of YT cells. Activation of the MEK/ERK signaling cascade occurs following uPAR crosslinking, as phosphorylation of both MEK 1/2 and ERK 1/2 results from receptor clustering. The MEK-specific inhibitors PD98059 and U0126 blocked MAP kinase phosphorylation; furthermore, PD98059 inhibited the increase in integrin expression induced by uPAR clustering. This study suggests that uPAR is a signaling receptor and regulator of integrins in NK cells and may impact NK cell function, including the potential for their accumulation within tumor metastases following adoptive transfer.
Gellert
Ginelle C
GC
Department of Molecular Biology and Immunology, and Institute for Cancer Research, University of North Texas Health Science Center at Fort Worth, Texas 76107, USA.
Kitson
Richard P
RP
Goldfarb
Ronald H
RH
D015153:Blotting, Western; D002460:Cell Line; D004789:Enzyme Activation; D005419:Flavonoids / Q000494:pharmacology; D005434:Flow Cytometry; D006801:Humans; D016023:Integrins / Q000378:metabolism*; D007694:Killer Cells, Natural / Q000378:metabolism*; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D011956:Receptors, Cell Surface / Q000378:metabolism*; D055293:Receptors, Urokinase Plasminogen Activator
D005419:Flavonoids; D016023:Integrins; C524898:PLAUR protein, human; D011956:Receptors, Cell Surface; D055293:Receptors, Urokinase Plasminogen Activator; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one