Kindlin‐2 interacts with α‐actinin‐2 and β1 integrin to maintain the integrity of the Z‐disc in cardiac muscles

Abstract

Edited by Dietmar J. Manstein Keywords:Kindlin-2 a-Actinin-2The Z-disc Cardiac structure a b s t r a c t Kindlin-2, as an integrin-interacting protein, was known to be required for the maintenance of cardiac structure and function in zebrafish. However, the mechanism remains unclear. We found that Kindlin-2 interacts and colocalizes with a-actinin-2 at the Z-disc of mouse cardiac muscles and there Kindlin-2 also interacts with b1 integrin. Knockdown of Kindlin-2 influences the association of b1 integrin with a-actinin-2 and disrupts the structure of the Z-disc and leads to cardiac dysfunction. Our data indicated that Kindlin-2 is a novel a-actinin-2-interacting protein and plays an important role in the regulation of cardiac structure and function.

Postnatal Loss of Kindlin-2 Leads to Progressive Heart Failure

“…Unlike Vinculin however, Kindlin-2 could not be detected at intercalated discs, nor did it co-localize with sarcomeric α-Actinin in isolated adult CMs. This result is in contrast with previous studies, which report that Kindlin-2 also localizes at intercalated discs 3 , and the Z-line 41 . We then proceeded to perform Western blot analyses of an array of proteins in heart tissue, concentrating on components of the integrin complex, adherens and gap junction, as well as the desmosome (Figure 3A and Supplementary Figure 1B–C).…”

“…Since Kindlin-2 is an integrin-interacting protein that binds to the integrin β cytoplasmic tail to promote integrin activation 19–21, 23, 41 , and since expression of UNC-112, the C. elegans homolog of mammalian Kindlin-2, is necessary for organization of β integrin homologs in the muscle cell membrane and for proper muscle attachment 15, 27 , we next investigated how loss of Kindlin-2 in CMs might affect integrin expression or function. First we determined the localization of Kindlin-2, by performing immunomicroscopy of CMs isolated from control mouse hearts (Supplementary Figure 1A), owing to lack of antibodies specific to Kindlin-2 for immunofluorescence studies on cardiac sections.…”

“…Previous studies showed that Kindlin-2 is localized at the Z-line where it interacts with α-Actinin 41 , and at the intercalated disc where it has been proposed to be critical for the establishment of myofibrillar attachments in cardiac and skeletal muscle 3 . In contrast to these observations, we only detected Kindlin-2 in the costamere of adult isolated CMs.…”

“…Aberrations in Kindlin-2 expression or activity may therefore potentially contribute to the pathogenesis of cardiomyopathy via Kindlin-2 interaction with integrins, or modulation of their signaling and mechanotransductive properties 7, 43, 44 . Kindlin-2 has previously been shown to bind to the integrin β cytoplasmic tail and promote integrin activation 13, 19–21, 23, 41, 45 . In this study, we provide further evidence that Kindlin-2 is essential for integrin function by regulating integrin β1D protein expression levels in adult CMs.…”

FERMT2 rs17125944 polymorphism with Alzheimer's disease risk: a replication and meta-analysis

“…Kindlin-2, as an integrin-interacting protein, is ubiquitously expressed and mediates integrin activation and integrin-mediated cell-extracellular matrix (ECM) interaction [7, 8]. A study has been showed that kindlin-2 participates in the angiogenesis of mice and zebrafish and mediating cardiac structure and function [9, 10]. FERMT2 also promotes breast cancer progression through activating genome instability [11].…”