HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Semaan, N. Articles by Sibilia, J. Search for Related Content PubMed PubMed Citation Articles by Semaan, N. Articles by Sibilia, J.

Etk/BMX, a Btk Family Tyrosine Kinase, and Mal Contribute to the Cross-Talk between MyD88 and FAK Pathways¹

Noha Semaan^*, Ghada Alsaleh^*, Jacques-Eric Gottenberg, Dominique Wachsmann^2,3,* and Jean Sibilia^2,

^* Laboratoire Physiopathologie des Arthrites, Université Louis Pasteur de Strasbourg, Unité de Formation et de Recherche Sciences Pharmaceutiques, Illkirch, France; Rhumatologie Institut National de la Santé et de la Recherche Médicale U802, Hôpital Bicêtre (Assistance Publique-Hôpitaux de Paris) Université Paris-Sud 11, Le Kremlin Bicêtre, France; and Département de Rhumatologie, Hôpitaux Universitaires de Strasbourg, Strasbourg, France

MyD88 and focal adhesion kinase (FAK) are key adaptors involved in signaling downstream of TLR2, TLR4, and integrin ₅β₁, linking pathogen-associated molecule detection to the initiation of proinflammatory response. The MyD88 and integrin pathways are interlinked, but the mechanism of this cross-talk is not yet understood. In this study we addressed the involvement of Etk, which belongs to the Tec family of tyrosine kinases, in the cross-talk between the integrin/FAK and the MyD88 pathways in fibroblast-like synoviocyte s (FLS) and in IL-6 synthesis. Using small interfering RNA blockade, we report that Etk plays a major role in LPS- and protein I/II (a model activator of FAK)-dependent IL-6 release by activated FLS. Etk is associated with MyD88, FAK, and Mal as shown by coimmunoprecipitation. Interestingly, knockdown of Mal appreciably inhibited IL-6 synthesis in response to LPS and protein I/II. Our results also indicate that LPS and protein I/II induced phosphorylation of Etk and Mal in rheumatoid arthritis FLS via a FAK-dependent pathway. In conclusion, our data provide support that, in FLS, Etk and Mal are implicated in the cross-talk between FAK and MyD88 and that their being brought into play is clearly dependent on FAK.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by grants from Bristol Myers Squibb, Roche, and Pfizer (to J.S.).

² J.S. and D.W. contributed equally to this work.

³ Address correspondence and reprint requests to Dr. Dominique Wachsmann, EA3432, Unité de Formation et de Recherche Sciences Pharmaceutiques, 74 Route du Rhin, 67401 Illkirch, France. E-mail address: dominique.wachsmann{at}pharma.u-strasbg.fr

⁴ Abbreviations used in this paper: PIP₂, phosphatidyl inositol 4,5-biphosphate; Btk, Bruton’s tyrosine kinase; FAK, focal adhesion kinase; FLS, fibroblast-like synoviocyte; PH, pleckstrin homology; RA, rheumatoid arthritis; siRNA, small interfering RNA.

This article has been cited by other articles:

				G. Alsaleh, G. Suffert, N. Semaan, T. Juncker, L. Frenzel, J.-E. Gottenberg, J. Sibilia, S. Pfeffer, and D. Wachsmann Bruton's Tyrosine Kinase Is Involved in miR-346-Related Regulation of IL-18 Release by Lipopolysaccharide-Activated Rheumatoid Fibroblast-Like Synoviocytes J. Immunol., April 15, 2009; 182(8): 5088 - 5097. [Abstract] [Full Text] [PDF]