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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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IMMUNOBIOLOGY
The c-Abl tyrosine kinase regulates actin remodeling at the immune synapse
Yanping Huang1,
Erin O. Comiskey1,
Renell S. Dupree1,
Shuixing Li1,
Anthony J. Koleske2, and
Janis K. Burkhardt1
1 Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia and University of Pennsylvania School of Medicine, Philadelphia, PA; and
2 Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT
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 nonreceptor tyrosine kinase regulates actin responses in nonhematopoietic 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 interleukin-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 2 proteins known to be important for controlling actin responses to T-cell receptor (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 immune synapse (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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