Kindlins are a group of proteins that have recently attracted attention for their ability to bind and activate integrins. Moreover, they have also been linked to inherited and acquired human diseases including Kindler syndrome, leukocyte adhesion deficiency, and cancer. Although most studies have focused on kindlins as key regulatory components of cell-extracellular matrix junctions such as focal adhesions, preliminary data suggest the involvement of additional cellular compartments in mediating their functions, particularly at cell-cell contacts and the nucleus. Investigating the many roles of kindlins is likely to expand and sharpen our view on the versatility of integrin-mediated cell adhesion, the nuclear function of focal adhesion proteins, and the crosstalk between cell-cell and cell-matrix adhesions in health and disease.
"Although a kindlin was first discovered in humans in 1994 (Wick et al., 1994), it was not until the description of UNC-112 in 2000 (Rogalski et al., 2000) that we learned that kindlins have a role in integrin adhesion complexes. In contrast to C. elegans, which has one kindlin (UNC-112), humans have three kindlins, each encoded by a separate gene (Meves et al., 2009). Inherited mutations in kindlin-1 result in a serious skin disease (Kindler syndrome) (Siegel et al., 2003), and mutations in kindlin-3 result in severe dysfunction of both platelets and leukocytes (leukocyte adhesion deficiency type III) (Moser et al., 2009; Svensson et al., 2009). "
[Show abstract][Hide abstract] ABSTRACT: We describe a strategy for exploring the function of protein-protein interactions in striated muscle in vivo. We describe our experience using this strategy to study the interaction of UNC-112 (kindlin) with PAT-4 (integrin linked kinase). Random mutagenesis is used to generate a collection of mutants that are screened for lack of binding or gain of binding using a yeast 2-hybrid assay. The mutant proteins are then expressed in transgenic C. elegans to determine their ability to localize in the sarcomere. We emphasize two advantages of this strategy: (1) for studying the interaction of protein A with protein B, when protein A can interact with multiple proteins, and (2) it explores the function of an interaction rather than the absence of, or reduced level of, a protein as can be obtained with null mutants or knockdown by RNAi. We propose that this method can be generalized for studying the meaning of a protein-protein interaction in muscle for any system in which transgenic animals can be generated and their muscles can be imaged.
Frontiers in Physiology 04/2014; 5:162. DOI:10.3389/fphys.2014.00162 · 3.53 Impact Factor
"Kindlin-2 has also been reported to bind to the TGF-β type 1 receptor through its FERM domain and to Smad3 through its N terminus , which mediates this interaction in human kidney tubular epithelial cells . Kindlin-1 and kindlin-2 have also been described to be found in the nucleus of cells; no such localization of kindlin-3 has so far been reported . "
[Show abstract][Hide abstract] ABSTRACT: Kindlin-3 is a member of the kindlin family of focal adhesion proteins which bind to integrin beta-chain cytoplasmic domains to regulate integrin function. In contrast to kindlin-1 and kindlin-2 proteins, kindlin-3 is expressed mainly in the hematopoietic system. Mutations in kindlin-3 result in the rare genetic disorder, leukocyte adhesion deficiency type III (LAD-III), which is characterized by bleeding and recurrent infections due to deficient beta1, beta2 and beta3 integrin activation in platelets and leukocytes. Here, we review the role of kindlin-3 in integrin activation and in different immune cell functions.
"Many integrins can tune their affinity for ligand by conformational changes, and the switch from the low- to the high-affinity conformation is called integrin activation . Integrin activation is promoted by the binding of talin-1 or talin-2 and any of the 3 kindlin isoforms to the cytoplasmic tail of the β-subunit –. The kindlins consist of an F0–F3 four-point-one/ezrin/radixin/moesin (FERM) domain, that contains the integrin-binding site in F3, and a pleckstrin homology (PH) domain inserted into F2. "
[Show abstract][Hide abstract] ABSTRACT: Loss-of-function mutations in the gene encoding the integrin co-activator kindlin-1 cause Kindler syndrome. We report a novel kindlin-1-deficient keratinocyte cell line derived from a Kindler syndrome patient. Despite the expression of kindlin-2, the patient's cells display several hallmarks related to reduced function of β1 integrins, including abnormal cell morphology, cell adhesion, cell spreading, focal adhesion assembly, and cell migration. Defective cell adhesion was aggravated by kindlin-2 depletion, indicating that kindlin-2 can compensate to a certain extent for the loss of kindlin-1. Intriguingly, β1 at the cell-surface was aberrantly glycosylated in the patient's cells, and its expression was considerably reduced, both in cells in vitro and in the patient's epidermis. Reconstitution with wild-type kindlin-1 but not with a β1-binding defective mutant restored the aberrant β1 expression and glycosylation, and normalized cell morphology, adhesion, spreading, and migration. Furthermore, the expression of wild-type kindlin-1, but not of the integrin-binding-defective mutant, increased the stability of integrin-mediated cell-matrix adhesions and enhanced the redistribution of internalized integrins to the cell surface. Thus, these data uncover a role for kindlin-1 in the regulation of integrin trafficking and adhesion turnover.
PLoS ONE 06/2013; 8(6):e65341. DOI:10.1371/journal.pone.0065341 · 3.23 Impact Factor
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