Svensson L, Howarth K, McDowall A et al.Leukocyte adhesion deficiency-III is caused by mutations in KINDLIN3 affecting integrin activation. Nat Med 15:306-312

Leukocyte Adhesion Laboratory, Cancer Research UK London Research Institute, 44 Lincoln's Inn Fields, London WC2A 3PX, UK.
Nature medicine (Impact Factor: 27.36). 03/2009; 15(3):306-12. DOI: 10.1038/nm.1931
Source: PubMed


Integrins are the major adhesion receptors of leukocytes and platelets. Beta1 and beta2 integrin function on leukocytes is crucial for a successful immune response and the platelet integrin alpha(IIb)beta3 initiates the process of blood clotting through binding fibrinogen. Integrins on circulating cells bind poorly to their ligands but become active after 'inside-out' signaling through other membrane receptors. Subjects with leukocyte adhesion deficiency-1 (LAD-I) do not express beta2 integrins because of mutations in the gene specifying the beta2 subunit, and they suffer recurrent bacterial infections. Mutations affecting alpha(IIb)beta3 integrin cause the bleeding disorder termed Glanzmann's thrombasthenia. Subjects with LAD-III show symptoms of both LAD-I and Glanzmann's thrombasthenia. Their hematopoietically-derived cells express beta1, beta2 and beta3 integrins, but defective inside-out signaling causes immune deficiency and bleeding problems. The LAD-III lesion has been attributed to a C --> A mutation in the gene encoding calcium and diacylglycerol guanine nucleotide exchange factor (CALDAGGEF1; official symbol RASGRP2) specifying the CALDAG-GEF1 protein, but we show that this change is not responsible for the LAD-III disorder. Instead, we identify mutations in the KINDLIN3 (official symbol FERMT3) gene specifying the KINDLIN-3 protein as the cause of LAD-III in Maltese and Turkish subjects. Two independent mutations result in decreased KINDLIN3 messenger RNA levels and loss of protein expression. Notably, transfection of the subjects' lymphocytes with KINDLIN3 complementary DNA but not CALDAGGEF1 cDNA reverses the LAD-III defect, restoring integrin-mediated adhesion and migration.

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    • "s cell membrane ( Kim et al . , 2011b ) . Kindlin ( which has three isoforms , kindlin - 1 , - 2 and - 3 ) has been found to cooperate with talin during integrin activation through direct binding to the b - integrin CT MD region ( Ma et al . , 2008 ; Moser et al . , 2008 ; Harburger et al . , 2009 ; Malinin et al . , 2009 ; Moser et al . , 2009b ; Svensson et al . , 2009 ; Bledzka et al . , 2012 ) . Studies on how talin changes integrin conformation have been focused on the b - integrin TM and CT domains , and have been described in many elegant reviews ( Moser et al . , 2009a ; Shattil et al . , 2010 ; Anthis and Campbell , 2011 ; Kim et al . , 2011b ; Calderwood et al . , 2013 ; Das et al . , 2014 ) ."
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    ABSTRACT: Studies on the mechanism of integrin inside-out activation have been focused on the role of β cytoplasmic tails that are relatively conserved and bear binding sites for the intracellular activators including talin and kindlin. Integrin α cytoplasmic tails share a conserved GFFKR motif at the membrane-proximal region forming specific interface with β membrane-proximal region that keeps integrin inactive. The α membrane-distal regions after the GFFKR motif are diverse both in length and sequence and their roles in integrin activation have not been well-defined. In this study, we report that the α cytoplasmic membrane-distal region contributes to maintaining integrin in the resting state and to integrin inside-out activation. Complete deletion of the α membrane-distal region diminished talin and kindlin mediated integrin ligand binding and conformational change. A proper length and amino acids of α membrane-distal region is important for integrin inside-out activation. Our data establish an essential role of the α integrin cytoplasmic membrane-distal region in integrin activation and provide new insights into how talin and kindlin induce the high affinity integrin conformation that is required for fully functional integrins.
    Full-text · Article · Mar 2015 · Journal of Cell Science
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    • "LAD type 1 and 2 mutations are rare and result in defects in leukocyte recruitment and severe recurrent infections in these patients (for a review, see van de Vijver et al. 2012). Leukocytes from patients that have mutations in kindlin-3 (FERMT3 gene), a cytosolic protein that binds to the cytoplasmic domains of β1, β2 and β3 integrins, fail to activate these three integrins and, as a result, emigrate poorly into tissues (Svensson et al. 2009). This disorder is called LAD type III. "
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    ABSTRACT: This issue of Tissue Barriers contains the inaugural special issue devoted to recent advances in barrier function of endothelial and epithelial cells. We used this opportunity to invite experts in vascular endothelial cell biology and epithelial cell biology to comment on critical questions and problems in permeability of organ and tissue barriers, and to provide insight into common areas in these fields, namely how these cells maintain homeostasis and response to injury and infection. To complement these reviews, this issue also contains four research articles that explore specific questions related respiratory and intestinal epithelial cell function.
    Full-text · Article · Feb 2015
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    • "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). Kindlin-2 is expressed in the heart and localized to intercalated disks and costameres. "
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    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.
    Full-text · Article · Apr 2014 · Frontiers in Physiology
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