Lymphocyte binding to MAdCAM-1 via alpha4beta7 integrin activates a signal transduction pathway involving tyrosine phosphorylation of paxillin and p105(Cas-L).
Alpha4beta7 integrin mediates lymphocyte trafficking to mucosal lymphoid organs by interacting with the mucosal vascular addressin MAdCAM-1. While the structural basis for the alpha4beta7 integrin-MAdCAM-1 interaction has been well characterized, less is known about the signal transduction pathways that regulate the alpha4beta7 integrin-mediated lymphocyte interaction with MAdCAM-1-expressing endothelial cells. Here we demonstrate that ligation of alpha4beta7 integrin with MAdCAM-1 induces a prominent tyrosine phosphorylation of paxillin and a 105-kDa protein (p105) that is reactive with an anti-p130(Cas) antibody, in the mouse T-cell line TK-1. Cloning and expression of a full-length cDNA encoding the mouse p105(Cas-L) revealed that the p105 molecule is a mouse ortholog of p105(Cas-L). We also demonstrated that crosslinking of alpha4beta7 integrin with MAdCAM-1 induces the rapid tyrosine phosphorylation of paxillin and p105(Cas-L) in normal lymphocytes and that PMA stimulation enhances the tyrosine phosphorylation of p105(Cas-L) but not of paxillin. These results suggest that intracellular signals initiated by alpha4beta7 integrin involve the tyrosine phosphorylation of paxillin and p105(Cas-L), which are differentially regulated, at least in part, by mechanisms that are PMA-sensitive or -insensitive.
Murata
Shinsuke
S
Laboratory of Molecular and Cellular Recognition, Osaka University Graduate School of Medicine (C8), 2-2, Yamada-oka, Suita 565-0871, Japan.
Tanaka
Toshiyuki
T
Miyasaka
Masayuki
M
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D001665:Binding Sites; D015815:Cell Adhesion Molecules; D002460:Cell Line; D002478:Cells, Cultured; D003598:Cytoskeletal Proteins / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D007136:Immunoglobulins / Q000378:metabolism*; D016023:Integrins / Q000378:metabolism*; D007700:Kinetics; D008214:Lymphocytes / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009088:Mucoproteins / Q000378:metabolism*; D051419:Paxillin; D010750:Phosphoproteins / Q000737:chemistry / Q000378:metabolism*; D010766:Phosphorylation; D019000:Phosphotyrosine / Q000378:metabolism; D015398:Signal Transduction; D014407:Tumor Cells, Cultured
D048868:Adaptor Proteins, Signal Transducing; D015815:Cell Adhesion Molecules; D003598:Cytoskeletal Proteins; D007136:Immunoglobulins; D016023:Integrins; C504265:MADCAM1 protein, human; C489082:Madcam1 protein, mouse; D009088:Mucoproteins; C099942:NEDD9 protein, human; C496061:PXN protein, human; D051419:Paxillin; D010750:Phosphoproteins; C496062:Pxn protein, mouse; C071777:integrin alpha4beta7; D019000:Phosphotyrosine