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Blood, 1 July 2008, Vol. 112, No. 1, pp. 111-119.
Prepublished online as a Blood First Edition Paper on February 27, 2008; DOI 10.1182/blood-2007-10-118232.
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Submitted October 15, 2007
Accepted February 12, 2008
The c-Abl tyrosine kinase regulates actin remodeling at the immune synapse
Yanping Huang, Erin O. Comiskey, Renell S. Dupree, Shuixing Li, Anthony J. Koleske, and Janis K. Burkhardt*
Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia and University of Pennsylvania School of Medicine, Philadelphia, PA, United States
Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT, United States
* Corresponding author; email: jburkhar{at}mail.med.upenn.edu.
Actin dynamics during T cell activation are controlled by the coordinate action of multiple actin regulatory proteins, functioning downstream of a complex network of kinases and other signaling molecules. The c-Abl non-receptor tyrosine kinase regulates actin responses in non-hematopoietic cells, but its function in T cells is poorly understood. Using kinase inhibitors, RNAi and conditional knockout mice, we investigated the role of c-Abl in controlling the T cell actin response. We find that c-Abl is required for normal actin polymerization and lamellipodial spreading at the immune synapse, and for downstream events leading to efficient IL-2 production. c-Abl also plays a key role in signaling chemokine-induced T cell migration. c-Abl is required for the appropriate function of two proteins known to be important for controlling actin responses to TCR engagement, the actin stabilizing adapter protein HS1 and the Rac1-dependent actin polymerizing protein WAVE2. c-Abl binds to phospho-HS1 via its SH2 domains and is required for full tyrosine phosphorylation of HS1 during T cell activation. In addition, c-Abl is required for normal localization of WAVE2 to the IS. These studies identify c-Abl as a key player in the signaling cascade leading to actin reorganization during T cell activation.
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