Journal
BIOCHEMICAL PHARMACOLOGY
Volume 86, Issue 6, Pages 770-781Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bcp.2013.07.024
Keywords
T cell receptor; Integrin; Focal adhesion kinase; RhoA; PF-562,271
Categories
Funding
- National Institutes of Health Grant NIAID R01 [AI068062]
- NIH [1R56AI094923-01]
- UW Institute on Aging Training Grant (NIH) [T32AG000213-17]
- American Cancer Society [122088-PF-12-050-01-CSM]
- University of Connecticut, Department of Pharmaceutical Sciences
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The focal adhesion kinase inhibitor, PF-562,271, is currently in clinical development for cancer, however it is not known how PF-562,271 affects T cell function. Here, we demonstrate inhibitory effects of PF-562,271 on the activation of primary human and mouse T cells. PF-562,271 inhibits T cell receptor signaling-induced T cell adhesion to intercellular adhesion molecule-1 and T cell interactions with antigen-presenting cells. An additional focal adhesion kinase inhibitor, PF-573,228, and genetic depletion of focal adhesion kinase also impair T cell conjugation with antigen-presenting cells. PF562,271 blocks phosphorylation of the signaling molecules zeta chain associate protein of 70 kDa, linker of activated T cells, and extracellular signal-regulated kinase, and impairs T cell proliferation. The effects observed on T cell proliferation cannot solely be attributed to focal adhesion kinase inhibition, as genetic depletion did not alter proliferation. The effect of PF-562,271 on T cell proliferation is not rescued when proximal T cell receptor signaling is bypassed by stimulation with phorbol-12-myristate-13-acetate and ionomycin. Taken together, our findings demonstrate that focal adhesion kinase regulates integrin-mediated T cell adhesion following T cell receptor activation. Moreover, our findings suggest that PF562,271 may have immunomodulatory effects that could impact its therapeutic applications. (C) 2013 Elsevier Inc. All rights reserved.
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