The focal adhesion kinase inhibitor PF-562,271 impairs primary CD4+ T cell activation.
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.
Department of Pharmaceutical Sciences, University of Connecticut, 69 North Eagleville Road, Unit 3092, Storrs, CT 06269, USA. andrew.wiemer@uconn.edu
Andrew J
AJ
Wiemer
Sarah A
SA
Wernimont
Thai-Duong
TD
Cung
David A
DA
Bennin
Hilary E
HE
Beggs
Anna
A
Huttenlocher
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D002450:Cell Communication / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D003713:Dendritic Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D018799:Intercellular Adhesion Molecule-1; D015759:Ionomycin / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000187:drug effects*; D051379:Mice; D008822:Mice, Transgenic; D010766:Phosphorylation; D061251:Primary Cell Culture; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D015363:Quinolones / Q000494:pharmacology; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013449:Sulfonamides / Q000494:pharmacology*; D013450:Sulfones / Q000494:pharmacology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
C521108:6-(4-(3-(methylsulfonyl)benzylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-3,4-dihydroquinolin-2(1H)-one; D007211:Indoles; C527797:N-methyl-N-(3-((2-(2-oxo-2,3-dihydro-1H-indol-5-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino)-methyl)-pyridin-2-yl)-methanesulfonamide; D047428:Protein Kinase Inhibitors; D015363:Quinolones; D011948:Receptors, Antigen, T-Cell; D013449:Sulfonamides; D013450:Sulfones; D018799:Intercellular Adhesion Molecule-1; D015759:Ionomycin; D051416:Focal Adhesion Protein-Tyrosine Kinases; D013755:Tetradecanoylphorbol Acetate
Focal adhesion kinase; Integrin; PF-562,271; RhoA; T cell receptor