Department of Medicine, University of California San Diego, La Jolla, California, USA.
Current opinion in hematology (Impact Factor: 3.97). 09/2011; 18(5):356-60. DOI: 10.1097/MOH.0b013e3283497f09
Source: PubMed


The modulation of integrin affinity is central to platelet and leukocyte function. Two proteins, talin and kindlin, that interact with distinct regions of integrin cytoplasmic domains, have been shown to play essential roles in inducing the high affinity integrin conformation required for platelet and leukocyte adhesive interactions.Here we highlight some of the key studies that have described roles for talin and kindlin in integrin function and discuss several models that explain how talin and kindlins might work together to regulate integrin activation.
Genetic deletion of kindlin-3 in mice results in platelet and leukocyte adhesive dysfunction associated with profoundly impaired activation of multiple classes of integrins, a phenotype similar to that observed in talin-deficient platelets and leukocytes. Since this initial report three years ago, numerous studies have provided important clues to how kindlins activate integrins and, in some cases, the relationship between kindlins and talin in integrin activation.
Clearly, talin and kindlins are key regulators of integrin affinity. Future experiments that define precisely how these molecules work in concert should provide important insights into the terminal signaling events that activate integrins.

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    • "The ability to activate Integrin is one of the most important and well-studied feature of Kindlins, which plays a significant role in Integrins inside out signaling. Integrin activation is known to be central in many important functions, e.g., cell-to-cell contact, cell spreading, cell migration and embryonic development (Rogalski et al., 2000; Shi et al., 2007; Ye and Petrich, 2011). Kindler syndrome is the first disease associated with Kindlins, which is a skin disease caused by mutation in Kindlin-1 coding region (Kindler, 1954; Has et al., 2011). "
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    ABSTRACT: Kindlin proteins represent a novel family of evolutionarily conserved FERM domain containing proteins (FDCPs) and are members of B4.1 superfamily. Kindlins consist of three conserved protein homologs in vertebrates: Kindlin-1, Kindlin-2 and Kindlin-3. All three homologs are associated with focal adhesions and are involved in integrin activation. FERM domain of each Kindlin is bipartite and plays a key role in integrin activation. A single ancestral Kindlin protein can be traced back to earliest metazoans, e.g., to Parazoa. This protein underwent multiple rounds of duplication in vertebrates, leading to the present Kindlin family. In this study, we trace phylogenetic and evolutionary history of Kindlin FERM domain with respect to FERM domain of other FDCPs. We show that FERM domain in Kindlin homologs is conserved among Kindlins but amount of conservation is less in comparison with FERM domain of other members in B4.1 superfamily. Furthermore, insertion of Pleckstrin Homology like domain in Kindlin FERM domain has important evolutionary and functional consequences. Important residues in Kindlins are traced and ranked according to their evolutionary significance. The structural and functional significance of high ranked residues is highlighted and validated by their known involvement in Kindlin associated diseases. In light of these findings, we hypothesize that FERM domain originated from a proto-Talin protein in unicellular or proto-multicellular organism and advent of multi-cellularity was accompanied by burst of FDCPs, which supported multi-cellularity functions required for complex organisms. This study helps in developing a better understanding of evolutionary history of FERM domain of FDCPs and the role of FERM domain in metazoan evolution.
    Full-text · Article · Aug 2014 · Molecular Phylogenetics and Evolution
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    • "These data also suggest that Zasp is not sufficient, by itself, to activate endogenous or overexpressed talin. The kindlins have also emerged as conserved regulators of integrin activation (Bouaouina and Calderwood, 2011; Meves et al., 2009; Ye and Petrich, 2011). However, while kindlins play an important role in muscle attachment in Drosophila, it is not known whether they impact bPS integrin activation (Bai et al., 2008), and despite considerable recent interest in kindlin function, the molecular basis for the effect of kindlins on mammalian integrins remains unknown. "
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    ABSTRACT: Integrins are heterodimeric adhesion receptors that link the extracellular matrix (ECM) to the cytoskeleton. Binding of the scaffold protein, talin, to the cytoplasmic tail of β integrin causes a conformational change of the extracellular domains of the integrin heterodimer, thus allowing high-affinity binding of ECM ligands. This essential process is called integrin activation. Here we report that the Z-band alternatively spliced PDZ-motif containing protein (Zasp) cooperates with talin to activate α5β1 integrins in mammalian tissue culture and αPS2βPS integrins in Drosophila. Zasp is a PDZ-LIM domain-containing protein mutated in human cardiomyopathies previously thought to function primarily in assembly and maintenance of the muscle contractile machinery. Notably, Zasp is the first protein shown to co-activate α5β1 integrins with talin and appears to do so in a manner distinct from known αIIbβ3 co-activators.
    Full-text · Article · Sep 2012 · Journal of Cell Science
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    • "Here we investigated whether kindlins influence talin recruitment to αIIbβ3, one of the hypotheses proposed to explain the mechanism of kindlin function [2], [20], [21], [25]. Using complementary approaches with intact cells and purified, recombinant proteins, we establish that kindlins do not promote talin recruitment to plasma membranes or to αIIbβ3. "
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    ABSTRACT: Talins and kindlins bind to the integrin β3 cytoplasmic tail and both are required for effective activation of integrin αIIbβ3 and resulting high-affinity ligand binding in platelets. However, binding of the talin head domain alone to β3 is sufficient to activate purified integrin αIIbβ3 in vitro. Since talin is localized to the cytoplasm of unstimulated platelets, its re-localization to the plasma membrane and to the integrin is required for activation. Here we explored the mechanism whereby kindlins function as integrin co-activators. To test whether kindlins regulate talin recruitment to plasma membranes and to αIIbβ3, full-length talin and kindlin recruitment to β3 was studied using a reconstructed CHO cell model system that recapitulates agonist-induced αIIbβ3 activation. Over-expression of kindlin-2, the endogenous kindlin isoform in CHO cells, promoted PAR1-mediated and talin-dependent ligand binding. In contrast, shRNA knockdown of kindlin-2 inhibited ligand binding. However, depletion of kindlin-2 by shRNA did not affect talin recruitment to the plasma membrane, as assessed by sub-cellular fractionation, and neither over-expression of kindlins nor depletion of kindlin-2 affected talin interaction with αIIbβ3 in living cells, as monitored by bimolecular fluorescence complementation. Furthermore, talin failed to promote kindlin-2 association with αIIbβ3 in CHO cells. In addition, purified talin and kindlin-3, the kindlin isoform expressed in platelets, failed to promote each other's binding to the β3 cytoplasmic tail in vitro. Thus, kindlins do not promote initial talin recruitment to αIIbβ3, suggesting that they co-activate integrin through a mechanism independent of recruitment.
    Full-text · Article · Mar 2012 · PLoS ONE
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