The kindlins at a glance.

Introduction The kindlin family of focal adhesion (FA) proteins consists of three evolutionarily conserved proteins, kindlin-1, -2 and -3 [also known as fermitin family homolog 1, 2 and 3 (FERM1, FERM2 and URP2), respectively], and was named after a rare congenital skin disease – the Kindler syndrome – which is caused by mutations in the gene encoding kindlin-1 (Jobard et al., 2003; Siegel et al., 2003). Kindlin-1 and kindlin-2 diverged from kindlin-3 during evolution and, therefore, share higher sequence identity (Siegel et al., 2003). The profound differences in tissue expression (see poster) suggest that the individual kindlin proteins acquired specific tasks during evolution. Kindlin-1 is mainly expressed in epithelial cells, such as keratinocytes or intestinal epithelial cells, whereas kindlin-2 is almost ubiquitously expressed. Kindlin-3 expression is restricted to the hematopoietic system (Meves et al., 2009; Ussar et al., 2006). A series of recent publications has highlighted the fundamental importance of the three kindlins for integrin function (Harburger et al., 2009; Ma et al., 2008; Montanez et al., 2008; Moser et al., 2009a; Moser et al., 2008; Ussar et al., 2008). Integrins are heterodimeric transmembrane receptors that mediate cellextracellular matrix (ECM) and cell-cell adhesions (Hynes, 2002). Integrin-mediated adhesion triggers integrin clustering and the assembly of signaling and adaptor proteins at their cytoplasmic domains, which convey biochemical signals into different cellular compartments and link the adhesion site to the actin cytoskeleton. This mode of integrin signaling is called ‘outside-in signaling’ (Legate et al., 2009). A hallmark of integrins is their ability to fine-tune their affinity for their ligands by switching their extracellular domain between several different conformations. The conformational change that increases the affinity of integrins for their ligands is believed to be controlled by proteins that bind to the short cytoplasmic tails of integrins. The recruitment of these ‘integrin activators’ can be triggered by a wide range of cell-surface receptors and the activation of associated signaling pathways. As this process, termed inside-out signaling or integrin activation, was thought to be exclusively mediated by talin (Tadokoro et al., 2353 Cell Science at a Glance