Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 291, Issue 50, Pages 26083-26097Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M116.757138
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- National Institutes of Health [GM106727, GM106727-S1]
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The chemokine receptor CXCR4 and its chemokine ligand CXCL12 mediate directed cell migration during organogenesis, immune responses, and metastatic disease. However, the mechanisms governing CXCL12/CXCR4-dependent chemotaxis remain poorly understood. Here, we show that the beta-arrestin1.signal-transducing adaptor molecule 1 (STAM1) complex, initially identified to govern lysosomal trafficking of CXCR4, also mediates CXCR4-dependent chemotaxis. Expression of mini-gene fragments from beta-arrestin1 or STAM1, known to disrupt the beta-arrestin1.STAM1 complex, and RNAi against beta-arrestin1 or STAM1, attenuates CXCL12-induced chemotaxis. The beta-arrestin1.STAM1 complex is necessary for promoting autophosphorylation of focal adhesion kinase (FAK). FAK is necessary for CXCL12-induced chemotaxis and associates with and localizes with beta-arrestin1 and STAM1 in a CXCL12-dependent manner. Our data reveal previously unknown roles in CXCR4-dependent chemotaxis for beta-arrestin1 and STAM1, which we propose act in concert to regulate FAK signaling. The beta-arrestin1.STAM1 complex is a promising target for blocking CXCR4-promoted FAK autophosphorylation and chemotaxis.
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