Focal adhesion kinase (FAK)‐related non‐kinase (FRNK) negatively regulates eosinophil recruitment (146.4)

Abstract

Focal adhesion kinase (FAK)‐related non‐kinase (FRNK) is an independently expressed protein containing the C‐terminal domain of FAK. A recent study showed that FRNK negatively regulates lung fibrosis. In this study we asked if FRNK could negatively regulate human eosinophil recruitment in response to IL‐4. Exogenous expression of FRNK blocked >90% of eosinophil firm adhesion and transmigration to IL‐4‐stimulated endothelial cells (HUVEC) under flow conditions. FRNK blocked eosinophil recruitment by preventing the transcription and translation of VCAM‐1 and eotaxin‐3 (CCL26), two proteins we previously showed were critical for eosinophil recruitment. GATA6 has been shown to regulate VCAM‐1 in response to TNF, but its role in IL‐4‐mediated VCAM‐1 expression is not known. We found the IL‐4 increased GATA6 expression and down‐regulating GATA6 with siRNA blocked VCAM‐1 expression and function. Expressing FRNK in HUVEC prevented GATA6 upregulation by IL‐4 suggesting that FRNK blocks VCAM‐1 expression through its actions on GATA6. FRNK can act directly by binding to target molecules or indirectly by displacing FAK at focal adhesions and blocking FAK’s kinase activity. To determine if FRNK was acting through FAK, we down‐regulated FAK with siRNA and found that knocking down FAK had no effect on GATA6, VCAM‐1 or CCL26 expression. These data suggest that FRNK acts independent of FAK to negatively regulate eosinophil recruitment.Grant Funding Source: Supported by the Canadian Institutes of Health Research