By means of its FERM (four point one ezrin, radixin and moesin) and pleckstrin homology (PH) domains (Fig. 10.1b), kindlin-1 is localised to integrin-linked adhesion sites and provides linkage of filamentous actin in the cell cortex to membrane proteins on the surface of cells [14, 15]. The FERM domain is subdivided in the subdomains F0–F3 and has high homology to the talin FERM domain [13] (Fig. 10.1b). The N-terminal F0 subdomain is required for integrin activation [16, 17], whereas the F3 subdomain interacts directly with β integrin cytoplasmic tails through phosphotyrosine binding folds [16, 18]. Using integrin pull-down assays, kindlin-1 was shown to bind to the membrane-distal NxxY motif and a preceding threonine-containing region in the C-terminus of β integrin cytoplasmic tails, thus modulating integrin activation [11, 19]. The interactions of kindlin-1 with migfilin, integrin-linked kinase, α-actinin and focal adhesion kinase may represent the link between integrins and the actin cytoskeleton [8, 11, 20]. In keratinocytes, kindlin-1 exists in two forms, non-phosphorylated and phosphorylated, and phosphorylation depends on casein kinase 2 [12]. In a global approach to identify proteins whose phosphorylation is cell cycle regulated, two serine (Ser170 and Ser179) phosphorylation sites were identified in kindlin-1 in HeLa cells [21] (Fig. 10.1b).

Integrins are members of a large family of functionally conserved receptors which play important roles in cell adhesion, migration, proliferation and survival [22]. Integrins activate intracellular signalling pathways after binding to their ligands (“outside-in” signalling), and they can shift from a low- to a high-affinity state for the ligands (“inside-out” signalling), which is known as “integrin activation” [15]. Talin and kindlins bind to integrin β subunit cytoplasmic tails and cause activation [15]. This is particularly important during development, in response to injury and during inflammation [15]. Deletion of kindlin-2 results in death at implantation, due to defective integrin function, in cells of the endoderm and epiblast [23, 24]. Integrin activation adjusts adhesion and migration of leucocytes and thrombocytes, and its ablation due to kindlin-3 loss-of-function mutations causes leucocyte adhesion deficiency-III with severe bleeding and life-threatening infections [25, 26]. The physiological significance of integrin activation in adult tissues composed of cells with stable adhesion, like the keratinocytes in the epidermis, might be different. Nevertheless, deletion of kindlin-1 significantly reduces integrin activation in intestinal epithelial cells and epidermal keratinocytes [11, 27, 28].

Talin and kindlins accomplish distinct functions in integrin activation [29, 30]. The two NPxY motifs of β1 integrin which serve as binding sites for talin and kindlins seem to play distinct roles in epithelial cells. Binding of talin to the membrane-proximal NPxY is crucial for connecting α5β1 to the actin cytoskeleton and thus permits the tension required for fibronectin fibrillogenesis and cell migration, whereas binding of kindlin to the membrane-distal NPxY regulates α5β1 surface expression and degradation [30]. The kindlin binding site in the β1 integrin cytoplasmic domain serves as a molecular switch enabling the sequential binding of two FERM-domain-containing proteins in different cellular compartments. When β1 integrins are at the plasma membrane, kindlins control ligand-binding affinity. However, when they are internalised, kindlins dissociate from integrins, which are recycled back to the cell surface [18].

Whether kindlins accomplish overlapping or distinct functions remains an interesting issue. Keratinocytes express both kindlin-1 and kindlin-2, but nonetheless, in the absence of kindlin-1 in Kindler syndrome, kindlin-2 cannot fully compensate and rescue the defect. Knockdown of either of the kindlins affects adhesion, survival and migration of the keratinocytes and integrin activation, suggesting that kindlins have overlapping functions. Beyond that, sole deficiency of kindlin-2 strongly impairs the formation of cell-cell adhesions [28]. Using integrin β1 knockout keratinocytes as a model, a further difference between kindlin-1 and kindlin-2 has been uncovered; while kindlin-1 and kindlin-2 both bind and co-localise with β1 integrins, only kindlin-1 binds with β6 integrins [10]. Nevertheless, the presence of at least one kindlin partially assures keratinocyte functions, whereas loss of both kindlins has a cumulative impact on cell adhesion, survival and migration and on integrin activation [28].

Another interesting finding regarding the interplay between kindlins was recently reported in neurons. Although in physiological conditions kindlin-2, but not kindlin-1, is present in the nervous system, expression of kindlin-1 enhances integrin activation and signalling and promotes axon regeneration and recovery of sensory functions after dorsal root crush [31].

The phenotype of the kindlin-1 knockout mice does not recapitulate the human disorder [11]. Animals appear normal at birth, but 2 days postnatal they become dehydrated, fail to thrive and die between postnatal days 3 and 5. The skin is atrophic with reduced keratinocyte proliferation, but adhesion of keratinocytes to the basement membrane, differentiation and epidermal barrier are not altered. Perinatal lethality is due to severe progressive intestinal dysfunction, with severe inflammation and more than 80 % of the colonic epithelium detached by postnatal day 3 [11].

Several lines of evidence implicate kindlin-1 in cancer. First, increased mRNA levels of the kindlin-1 gene, FERMT1, were found in 60 % of lung and 70 % of colon cancers [32]. Second, FERMT1 is a TGF-β1 inducible gene, and its overexpression increases cell spreading and associates with epithelial to mesenchymal transition in HMEC (human mammary epithelial cells) [13]. Third, FERMT1 was identified as a gene associated with breast cancer lung metastasis [33], and there is evidence that kindlin-1 could also be an important mediator of lung metastasis in breast cancer and other cancer types metastasising to the lung [34].