Characterization of a novel focal adhesion kinase inhibitor in human platelets

ML Jones, AJ Shawe-Taylor, CM Williams, AW Poole

Research output: Contribution to journalArticle (Academic Journal)peer-review

22 Citations (Scopus)

Abstract

Focal adhesion kinase (FAK) is activated in human platelets downstream of integrins, e.g. alpha(IIb)beta(3), and other adhesion receptors e.g. GPVI. Mice in which platelets lack FAK have been shown to exhibit extended bleeding times and their platelets have been shown to display decreased spreading on fibrinogen-coated surfaces. Recently, a novel FAK inhibitor (PF-573,228) has become available, its selectivity for FAK shown in vitro and in cell lines. We determined the effect of this inhibitor on platelet function and signaling pathways. Like murine platelets lacking FAK, we found that PF-573,228 was effective at blocking human platelet spreading on fibrinogen-coated surfaces but did not affect the initial adhesion. We also found a reduced spreading on CRP-coated surfaces. Further analysis of the morphology of platelets adhered to these surfaces showed the defect in spreading occurred at the transition from filopodia to lamellipodia. Similar to that seen with murine neutrophils lacking FAK, we also observed an unexpected defect in intracellular calcium release in human platelets pre-treated with PF-573,228 which correlated with impaired dense granule secretion and aggregation. The aggregation defect could be partially rescued by addition of ADP, normally secreted from dense granules, suggesting that PF-573,228 has effects on FAK downstream of alpha(IIb)beta(3) and elsewhere. Our data show that PF-573,228 is a useful tool for analysis of FAK function in cells and reveal that in human platelets FAK may regulate a rise in cell calcium and platelet spreading.
Translated title of the contributionCharacterization of a novel focal adhesion kinase inhibitor in human platelets
Original languageEnglish
Pages (from-to)198 - 203
JournalBiochemical and Biophysical Research Communications
Volume389(1)
Publication statusPublished - Nov 2009

Bibliographical note

Author of Publication Reviewed: Jones ML, Shawe-Taylor AJ, Williams CM, Poole AW

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