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Deficiency in the LIM-only protein FHL2 impairs assembly of extracellular matrix proteins

Jung Park^,1, Carola Will^*,1, Bernd Martin, Lucia Gullotti^,2, Nicolaus Friedrichs, Reinhard Buettner, Holm Schneider^||, Stephan Ludwig^* and Viktor Wixler^*,3

^* Institute of Molecular Virology, Münster University Hospital Medical School, Münster, Germany;

Department of Experimental Medicine I, University of Erlangen-Nürnberg, Erlangen, Germany;

Department of Gynecology and Obstetrics, Medical School, J. W. Goethe-University, Frankfurt, Germany;

Institute of Pathology, University Hospital Medical School, Bonn, Germany;

^|| Experimental Neonatology, Department of Pediatrics, Medical University of Innsbruck, Innsbruck, Austria

³Correspondence: Institute of Molecular Virology, Münster University Hospital Medical School, Von-Esmarch-Str. 56, D-48149 Münster, Germany. E-mail: vwixler{at}uni-muenster.de

We have described the scaffolding protein FHL2 as a component of focal adhesion structures, to which it is recruited via binding to both - or β-integrin subunits. Using mesenchymal stem cells from wild-type and FHL2-knockout mice, we show here that inactivation of FHL2 leads to impaired assembly of extracellular matrix proteins on the cell surface and to impaired bundling of focal adhesions. Both altered properties can be restored by reexpression of recombinant FHL2 protein in FHL2-null cells. Molecular analysis of integrin-mediated signaling revealed a higher phosphorylation of FAK at tyrosine 925 in FHL2-knockout cells compared to their wild-type counterpart. Consequently, the activation of the mitogenic kinase ERK was more pronounced in knockout cells on cell adhesion. The growth factor-induced activation of ERK, however, was not altered. The perturbed organization of extracellular matrix on FHL2-null cells was improved when the increased activation of MAPK was inhibited. Our findings point to a role of FHL2 in bundling of focal adhesion structures, in integrin-mediated ERK activation, and subsequently in proper allocation of matrix proteins on the cell surface.—Park, J., Will, C., Martin, B., Gullotti, L., Friedrichs, N., Buettner, R., Schneider, H., Ludwig, S., Wixler, V. Deficiency in the LIM-only protein FHL2 impairs assembly of extracellular matrix proteins.

Key Words: fibronectin • integrin-mediated ERK activation • focal adhesions • cytoskeleton