The focal adhesion kinase inhibitor PF-562,271 impairs primary CD4+ T cell activation

Andrew J. Wiemer, Sarah A. Wernimont, Thai D. Cung, David A. Bennin, Hilary E. Beggs, Anna Huttenlocher

Research output: Contribution to journalArticlepeer-review

14 Scopus citations

Abstract

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. PF-562,271 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 PF-562,271 may have immunomodulatory effects that could impact its therapeutic applications.

Original languageEnglish (US)
Pages (from-to)770-781
Number of pages12
JournalBiochemical Pharmacology
Volume86
Issue number6
DOIs
StatePublished - 2013
Externally publishedYes

Bibliographical note

Funding Information:
We thank Miriam Shelef for phlebotomy assistance and Danny Grahf for genotyping assistance. This work was supported by National Institutes of Health Grant NIAID R01 to A.H. [AI068062] and NIH 1R56AI094923-01 to A.H. Postdoctoral support was provided to A.J.W. by the UW Institute on Aging Training Grant ( NIH#T32AG000213-17 ), Sanjay Asthana PI and by Postdoctoral Fellowship #122088-PF-12-050-01-CSM from the American Cancer Society . Support was also provided to A.J.W. by internal funding from the University of Connecticut, Department of Pharmaceutical Sciences .

Keywords

  • Focal adhesion kinase
  • Integrin
  • PF-562,271
  • RhoA
  • T cell receptor

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