Kindlin-1 is an epithelial-specific member of the novel kindlin protein family, which are regulators of integrin functions. Mutations in the gene that encodes Kindlin-1, FERMT1 (KIND1), cause the Kindler syndrome (KS), a human disorder characterized by mucocutaneous fragility, progressive skin atrophy, ulcerative colitis, photosensitivity, and propensity to skin cancer. Our previous studies indicated that loss of kindlin-1 resulted in abnormalities associated with integrin functions , such as adhesion , proliferation , polarization , and motility of epidermal cells. Here , we disclosed novel FERMT1 mutations in KS and used them, in combination with small-interfering RNA, protein, and imaging studies, to uncover new functions for kindlin-1 in keratinocytes and to discern the molecular pathology of KS. We show that kindlin-1 forms molecular complexes with ␤1 integrin, ␣-actinin, migfilin, and focal adhesion kinase and regulates cell shape and migration by controlling lamellipodia formation. Kindlin-1 governs these processes by signaling via Rho family GTPases, and it is required to maintain the pool of GTP-bound, active Rac1, RhoA and Cdc42, and the phosphorylation of their downstream effectors p21-activated kinase 1, LIM kinase, and cofilin. Loss of these kindlin-1 functions forms the biological basis for the epithelial cell fragility and atrophy in the pathology of KS. (Am J

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Two integrins, alpha3beta1 and alpha6beta4, are high-affinity receptors for laminin 332, the major laminin isoform of the dermal-epidermal junction, although they are thought to have different functions. Biological and genetic studies have firmly established that the alpha6beta4 integrin is indispensable for the stable anchorage of the epidermis to the underlying dermis. In contrast, the alpha3beta1 integrin is thought to be important for cell migration, although the issue is controversial, and both positive and negative effects have been reported. To address the function of alpha3beta1 integrin, we used small interfering RNA to down-regulate the alpha3 subunit in human keratinocytes. The resulting phenotype indicates that lack of alpha3beta1 integrin compromises intercellular adhesion and collective migration, while it enhances single cell migration with a concomitant increase of both focal adhesion kinase and extracellular signal-regulated kinase. In addition, down-regulation of integrin alpha3 subunit results in an increased expression of fibronectin and precursor laminin 332, two extracellular matrix proteins known to be up-regulated during wound healing. Thus, down-regulation of alpha3beta1 integrin recapitulates crucial events governing keratinocyte migration associated with wound healing and tissue repair.

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