title: β-Arrestin1 and Signal-transducing Adaptor Molecule 1 (STAM1) Cooperate to Promote Focal Adhesion Kinase Autophosphorylation and Chemotaxis via the Chemokine Receptor CXCR4.
abstract: 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 β-arrestin1·signal-transducing adaptor molecule 1 (STAM1) complex, initially identified to govern lysosomal trafficking of CXCR4, also mediates CXCR4-dependent chemotaxis. Expression of minigene fragments from β-arrestin1 or STAM1, known to disrupt the β-arrestin1·STAM1 complex, and RNAi against β-arrestin1 or STAM1, attenuates CXCL12-induced chemotaxis. The β-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 β-arrestin1 and STAM1 in a CXCL12-dependent manner. Our data reveal previously unknown roles in CXCR4-dependent chemotaxis for β-arrestin1 and STAM1, which we propose act in concert to regulate FAK signaling. The β-arrestin1·STAM1 complex is a promising target for blocking CXCR4-promoted FAK autophosphorylation and chemotaxis.
authors: From the Department of Biochemistry, Medical College of Wisconsin, Milwaukee, Wisconsin 53226.
authors: Olga
authors: O
authors: Alekhina
authors: From the Department of Biochemistry, Medical College of Wisconsin, Milwaukee, Wisconsin 53226 amarchese@mcw.edu.
authors: Adriano
authors: A
authors: Marchese
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D054377:Chemokine CXCL12 / Q000235:genetics / Q000378:metabolism; D002633:Chemotaxis / Q000502:physiology*; D056827:Endosomal Sorting Complexes Required for Transport / Q000235:genetics / Q000378:metabolism*; D051417:Focal Adhesion Kinase 1 / Q000235:genetics / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism*; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation / Q000502:physiology; D019718:Receptors, CXCR4 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D000071559:beta-Arrestin 1 / Q000235:genetics / Q000378:metabolism*
chemical_list: C000605253:ARRB1 protein, human; D048868:Adaptor Proteins, Signal Transducing; C515255:CXCL12 protein, human; C527276:CXCR4 protein, human; D054377:Chemokine CXCL12; D056827:Endosomal Sorting Complexes Required for Transport; D046912:Multiprotein Complexes; D010750:Phosphoproteins; D019718:Receptors, CXCR4; C109775:STAM protein, human; D000071559:beta-Arrestin 1; D051417:Focal Adhesion Kinase 1; C496050:PTK2 protein, human
keywords: C-X-C chemokine receptor type 4 (CXCR-4); CXCL12; G protein-coupled receptor (GPCR); PTK2 protein tyrosine kinase 2 (PTK2) (focal adhesion kinase) (FAK); STAM; chemokine; chemotaxis; β-arrestin