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.