title: FRNK negatively regulates IL-4-mediated inflammation.
abstract: Focal adhesion kinase (FAK)-related nonkinase (PTK2 isoform 6 in humans, hereafter referred to as FRNK) is a cytoskeletal regulatory protein that has recently been shown to dampen lung fibrosis, yet its role in inflammation is unknown. Here, we show for the first time that expression of FRNK negatively regulates IL-4-mediated inflammation in a human model of eosinophil recruitment. Mechanistically, FRNK blocks eosinophil accumulation, firm adhesion and transmigration by preventing transcription and protein expression of VCAM-1 and CCL26. IL-4 activates STAT6 to induce VCAM-1 and CCL26 transcription. We now show that IL-4 also increases GATA6 to induce VCAM-1 expression. FRNK blocks IL-4-induced GATA6 transcription but has little effect on GATA6 protein expression and no effect on STAT6 activation. FRNK can block FAK or Pyk2 signaling and we, thus, downregulated these proteins using siRNA to determine whether signaling from either protein is involved in the regulation of VCAM-1 and CCL26. Knockdown of FAK, Pyk2 or both had no effect on VCAM-1 or CCL26 expression, which suggests that FRNK acts independently of FAK and Pyk2 signaling. Finally, we found that IL-4 induces the late expression of endogenous FRNK. In summary, FRNK represents a novel mechanism to negatively regulate IL-4-mediated inflammation.
authors.affiliation: Department of Physiology and Pharmacology, University of Calgary; Calgary, AB T2N 4N1, Canada.
authors.forename: Ritu
authors.initials: R
authors.lastname: Sharma
authors.affiliation: Department of Physiology and Pharmacology, University of Calgary; Calgary, AB T2N 4N1, Canada The Snyder Institute for Chronic Diseases, University of Calgary, Calgary, AB T2N 4N1, Canada.
authors.forename: Pina
authors.initials: P
authors.lastname: Colarusso
authors.affiliation: Department of Physiology and Pharmacology, University of Calgary; Calgary, AB T2N 4N1, Canada.
authors.forename: Hong
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Department of Physiology and Pharmacology, University of Calgary; Calgary, AB T2N 4N1, Canada The Snyder Institute for Chronic Diseases, University of Calgary, Calgary, AB T2N 4N1, Canada.
authors.forename: Katarzyna M
authors.initials: KM
authors.lastname: Stevens
authors.affiliation: Department of Physiology and Pharmacology, University of Calgary; Calgary, AB T2N 4N1, Canada The Snyder Institute for Chronic Diseases, University of Calgary, Calgary, AB T2N 4N1, Canada Biochemistry and Molecular Biology, University of Calgary, Calgary, AB T2N 4N1, Canada kpatel@ucalgary.ca.
authors.forename: Kamala D
authors.initials: KD
authors.lastname: Patel
mesh_terms: D002448:Cell Adhesion / Q000276:immunology; D002465:Cell Movement / Q000276:immunology; D002478:Cells, Cultured; D000075906:Chemokine CCL26; D019742:Chemokines, CC / Q000096:biosynthesis; D004789:Enzyme Activation; D004804:Eosinophils / Q000276:immunology; D051417:Focal Adhesion Kinase 1 / Q000235:genetics / Q000378:metabolism; D051418:Focal Adhesion Kinase 2 / Q000235:genetics / Q000378:metabolism; D050993:GATA6 Transcription Factor / Q000096:biosynthesis / Q000235:genetics; D015870:Gene Expression / Q000235:genetics; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D007249:Inflammation / Q000276:immunology*; D018836:Inflammation Mediators / Q000378:metabolism*; D015847:Interleukin-4 / Q000276:immunology*; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering; D050800:STAT6 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology; D014158:Transcription, Genetic / Q000235:genetics; D019010:Vascular Cell Adhesion Molecule-1 / Q000096:biosynthesis
chemical_list: C120429:CCL26 protein, human; D000075906:Chemokine CCL26; D019742:Chemokines, CC; D050993:GATA6 Transcription Factor; C494759:GATA6 protein, human; C508598:IL4 protein, human; D018836:Inflammation Mediators; D034741:RNA, Small Interfering; D050800:STAT6 Transcription Factor; C494101:STAT6 protein, human; D019010:Vascular Cell Adhesion Molecule-1; D015847:Interleukin-4; C113183:FAK-related nonkinase; D011505:Protein-Tyrosine Kinases; D051417:Focal Adhesion Kinase 1; D051418:Focal Adhesion Kinase 2; C496050:PTK2 protein, human
keywords: Cell adhesion; Endothelial cells; Inflammation; Leukocyte trafficking