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J. Biol. Chem., Vol. 281, Issue 47, 36082-36090, November 24, 2006

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Kindlin-1 Is a Phosphoprotein Involved in Regulation of Polarity, Proliferation, and Motility of Epidermal Keratinocytes^*

Corinna Herz, Monique Aumailley^¶||, Carsten Schulte^¶, Ursula Schlötzer-Schrehardt^**, Leena Bruckner-Tuderman, and Cristina Has¹

From the Department of Dermatology, University Medical Center Freiburg, Hauptstrasse 7, 79104 Freiburg, Germany, Institute of Biology, University of Freiburg, Schänzlestrasse 1, 79104 Freiburg, Germany, ^¶Center for Biochemistry, University of Cologne, Joseph-Stelzmann-strasse 52, 50931 Cologne, Germany, ^||Center for Molecular Medicine Cologne, University of Cologne, Joseph-Stelzmann-strasse 52, 50931 Cologne, Germany, and the ^**Department of Ophthalmology, University of Erlangen, Schwabachanlage 6, 91054 Erlangen, Germany

A novel family of focal adhesion proteins, the kindlins, is involved in attachment of the actin cytoskeleton to the plasma membrane and in integrin-mediated cellular processes. Deficiency of kindlin-1, as a result of loss-of-function mutations in the KIND1 gene, causes Kindler syndrome, an autosomal recessive genodermatosis characterized by skin blistering, progressive skin atrophy, photosensitivity and, occasionally, carcinogenesis. Here we characterized authentic and recombinantly expressed kindlin-1 and show that it is localized in basal epidermal keratinocytes in a polar fashion, close to the cell surface facing the basement membrane, in the areas between the hemidesmosomes. We identified two forms of kindlin-1 in keratinocytes, with apparent molecular masses of 78 and 74 kDa, corresponding to phosphorylated and desphosphorylated forms of the protein. In kindlin-1-deficient skin, basal keratinocytes show multiple abnormalities: cell polarity is lost, proliferation is strongly reduced, and several cells undergo apoptosis. In vitro, deficiency of kindlin-1 in keratinocytes leads to strongly reduced cell proliferation, decreased adhesion, undirected motility, and intense protrusion activity of the plasma membrane. Taken together, these results show that kindlin-1 plays a role in keratinocyte adhesion, polarization, proliferation, and migration. It is involved in organization and anchorage of the actin cytoskeleton to integrin-associated signaling platforms.

Received for publication, June 29, 2006 , and in revised form, August 15, 2006.

^* This work was supported in part by a grant from Research Commission of the Medical Faculty of the University of Freiburg and the ROSA Skin Research Award (to C. H.), by the Network Epidermolysis bullosa grant from the Federal Ministry for Education and Research (BMBF), projects 5 and 9, and by ZMMK Grant TV80 (to M. A.). 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 To whom correspondence should be addressed. Tel.: 49-761-270-6785; Fax: 49-761-270-6720; E-mail: crishas{at}haut.ukl.uni-freiburg.de.

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