The role of kindlins in cell biology and relevance to human disease

Abstract

The kindlins represent a class of focal adhesion proteins implicated in integrin activation. They comprise three evolutionarily conserved members, kindlin-1, kindlin-2 and kindlin-3, that share considerable sequence and structural similarities. The kindlins have a bipartite FERM (four point one protein, ezrin, radixin, moesin) domain interrupted by a pleckstrin homology domain and can bind directly to various classes of integrins as well as participate in inside–out integrin activation. They are encoded by three different genes, namely KIND1 (FERMT1; chromosome 20p12.3), KIND2 (FERMT2; chromosome 14q22.1) and KIND3 (FERMT3; chromosome 11q13.1). Loss-of-function mutations in KIND1 and KIND3 cause Kindler syndrome and leukocyte adhesion deficiency-III syndrome, respectively, although no human disease has yet been associated with KIND2 gene pathology. In this review, we focus on the cellular functions of the kindlins and their clinical relevance.

Introduction

Integrins are glycosylated transmembrane heterodimeric adhesion receptors consisting of an α and a β subunit. They connect the cell to the external environment and mediate bidirectional signaling across the cell membrane (Hynes, 2002). Each integrin subunit consists of a large extracellular domain of about 700 amino acid residues (80–150 kDa), a single transmembrane α helix (∼20 residues) and a short cytoplasmic domain of about 10–70 residues. In eukaryotes, there are 18 α and 8 β subunits which non-covalently heterodimerize to form 24 distinct integrins (Hynes, 2002). Integrins are key components of focal adhesions and represent dynamic protein complexes involved in cell migration and adhesion. The extracellular domain of integrins interacts with extracellular matrix (ECM) proteins such as fibronectin and laminins while the short cytoplasmic tails mediate connections with the actin cytoskeleton via adaptor proteins such as talin. In addition to providing a dynamic interaction with the ECM, integrins are involved in several signaling pathways and are therefore able to regulate key cellular processes such as migration, differentiation, apoptosis and gene expression. An important step in integrin activation is the binding of the FERM (four point one protein, ezrin, radixin and moesin) domain of talin to the cytoplasmic tail of integrin (Calderwood, 2004b, Calderwood et al., 1999, Nieswandt et al., 2007, Petrich et al., 2007a, Petrich et al., 2007b, Vinogradova et al., 2004, Wegener et al., 2007). It is being increasingly recognized that other proteins may also regulate integrin activation. In this review, we discuss the cellular roles of a class of proteins called the kindlins and their role in integrin signaling and in the pathophysiology of human diseases.