Of Kindlins and Cancer

Abstract

Kindlins are 4.1-ezrin-ridixin-moesin (FERM) domain containing proteins. There are three kindlins in mammals, which share high sequence identity. Kindlin-1 is expressed primarily in epithelial cells, kindlin-2 is widely distributed and is particularly abundant in adherent cells, and kindlin-3 is expressed primarily in hematopoietic cells. These distributions are not exclusive; some cells express multiple kindlins, and transformed cells often exhibit aberrant expression, both in the isoforms and the levels of kindlins. Great interest in the kindlins has emerged from the recognition that they play major roles in controlling integrin function. In vitro studies, in vivo studies of mice deficient in kindlins, and studies of patients with genetic deficiencies of kindlins have clearly established that they regulate the capacity of integrins to mediate their functions. Kindlins are adaptor proteins; their function emanate from their interaction with binding partners, including the cytoplasmic tails of integrins and components of the actin cytoskeleton. The purpose of this review is to provide a brief overview of kindlin structure and function, a consideration of their binding partners, and then to focus on the relationship of each kindlin family member with cancer. In view of many correlations of kindlin expression levels and neoplasia and the known association of integrins with tumor progression and metastasis, we consider whether regulation of kindlins or their function would be attractive targets for treatment of cancer.

Kindlin-2 Regulates the Growth of Breast Cancer Tumors by Activating CSF-1–Mediated Macrophage Infiltration

“…Kindlins are members of the 4.1- ezrin-ridixin-moesin (FERM) domain containing proteins (7). Kindlins contain F1, F2 and F3 subdomains typical of FERM domain proteins that follow an N-terminal F0 subdomain and a pleckstrin homology (PH) subdomain that transects F2 subdomain.…”

“…Kindlins contain F1, F2 and F3 subdomains typical of FERM domain proteins that follow an N-terminal F0 subdomain and a pleckstrin homology (PH) subdomain that transects F2 subdomain. The three mammalian kindlin family members (Kindlin-1:FERMT1; Kindlin-2:FERMT2 and Kindlin-3:FERMT3) are highly homologous, sharing ~60% amino acid sequence identity (7). The adaptor functions of kindlins allow them to regulate numerous cellular responses.…”

“…The adaptor functions of kindlins allow them to regulate numerous cellular responses. Of particular importance is their capacity to regulate integrin activation, and integrin-dependent cell adhesion, spreading and migration (7–11). Kindlin-2, as well as its homologues, Kindlin-1 and Kindlin-3, has been linked to the malignancy of several types of cancers (reviewed in (7, 8)).…”

“…Of particular importance is their capacity to regulate integrin activation, and integrin-dependent cell adhesion, spreading and migration (7–11). Kindlin-2, as well as its homologues, Kindlin-1 and Kindlin-3, has been linked to the malignancy of several types of cancers (reviewed in (7, 8)). However, despite a few reports implicating Kindlin-2 in BC (12–15), a molecular mechanism by which Kindlin-2 contributes to the pathogenesis of BC is presumed to be dependent on its activation of tumor cell integrins, but its role in regulating tumor cell-stromal interactions has not been considered.…”

Integrins in the Spotlight of Cancer

“…Kindlins (kindlin-1, kindlin-2 and kindling-3) are other intracellular proteins of primordial importance in the modulation of integrin affinity [36]. These proteins are located at focal adhesion sites bound to the integrin cytoplasmic β tails and to the cytoskeleton and are essential for integrin signaling [37]. Loss of kindlins leads to integrin signaling dysregulation.…”