Role of leukocyte specific adaptor protein leupaxin in T cell migration

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Although the adhesion and locomotion of leukocytes largely depend on integrins, leukocytes often lack the distinguishable focal adhesions (FAs) that serve as signaling centers in other adherent cells. The assembly and disassembly of FAs is regulated by locally produced intracellular signals, and tyrosine phosphorylation of paxillin has been implicated in this process. Aleukocyte-specific adaptor protein, leupaxin, is a member of the paxillin family and shares overall structural characteristics with paxillin. Leupaxin is composed of multiple functional trbodules, including LD motifs and LIM domains, suggesting that leupaxin also serves as a molecular adaptor that is involved in integrinmediated signaling. However, it remains unknown whether leupaxin and paxillin cooperate with or antagonize each other in integrin signaling. We found that leupaxin potently represses the tyrosine phosphorylation of paxillin. When expressed in mouse thymoma BW5147 cells bound to ICAM-1, leupaxin accumulate … More d in FA like patches in the cell periphery In BW5147 cells migrating on ICAM-1, leupaxin is selectively located at the trailing edge. When expressed in NIH3T3 and HEK293Tcells, leupaxin localized to FAs upon cell adhesion to fibronectin and strongly suppressed the integrin-induced tyrosine phosphorylation of paxillin. In integrin-stimulatecd HEK293Tcells, leupaxin's LIM3 domain appeared essential for the selective FA localization and the suppression of paxillin tyrosine phosphorylation. Leupaxin's LD3 motif, which is critical for stable association with FAK, was dispensable for leupaxin's suppressive ability. In addition, leupaxin reduced the spreading of NIH3T3 cells on fibronectin, which required both the LD3 motif and LIM3 domain. When expressed in human leukocytic K562 cells, leupaxin significantly suppressed integrin α5β1-mediated cell adhesion to fibronectin and the tyrosine phosphorylation of paxillin. These findings indicate that leupaxin functions as a leukocyte-specific counterpart that potently suppresses the tyrosine phosphorylarion of paxillin during integrin signaling Less