Abl family kinases modulate T cell-mediated inflammation and chemokine-induced migration through the adaptor HEF1 and the GTPase Rap1.
Chemokine signaling is critical for T cell function during homeostasis and inflammation and directs T cell polarity and migration through the activation of specific intracellular pathways. Here, we uncovered a previously uncharacterized role for the Abl family tyrosine kinases Abl and Arg in the regulation of T cell-dependent inflammatory responses and showed that the Abl family kinases were required for chemokine-induced T cell polarization and migration. Our data demonstrated that Abl and Arg were activated downstream of chemokine receptors and mediated the chemokine-induced tyrosine phosphorylation of human enhancer of filamentation 1 (HEF1), an adaptor protein that is required for the activity of the guanosine triphosphatase Rap1, which mediates cell adhesion and migration. Phosphorylation of HEF1 by Abl family kinases and activation of Rap1 were required for chemokine-induced T cell migration. Mouse T cells that lacked Abl and Arg exhibited defective homing to lymph nodes and impaired migration to sites of inflammation. These findings suggest that Abl family kinases are potential therapeutic targets for the treatment of T cell-dependent immune disorders that are characterized by chemokine-mediated inflammation.
Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC 27710, USA.
Jing Jin
JJ
Gu
Catherine P
CP
Lavau
Elena
E
Pugacheva
Erik J
EJ
Soderblom
M Arthur
MA
Moseley
Ann Marie
AM
Pendergast
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D015153:Blotting, Western; D002448:Cell Adhesion / Q000276:immunology; D002465:Cell Movement / Q000276:immunology*; D018925:Chemokines / Q000378:metabolism*; D006160:Guanosine Triphosphate / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000276:immunology*; D051379:Mice; D010750:Phosphoproteins / Q000378:metabolism*; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D015398:Signal Transduction / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology*; D059008:Time-Lapse Imaging
D048868:Adaptor Proteins, Signal Transducing; D018925:Chemokines; C099942:NEDD9 protein, human; D010750:Phosphoproteins; D006160:Guanosine Triphosphate; C426236:ARG tyrosine kinase; D011505:Protein-Tyrosine Kinases