A Suppressive Role of Mitogen Inducible Gene-2 in Mesenchymal Cancer Cell Invasion

Abstract

Cancer cell invasion of extracellular matrix (ECM) is essential for dissemination of cancer cells and metastasis. In this study, we have investigated the role of mitogen inducible gene-2 (Mig-2, also known as kindlin-2), a focal adhesion protein whose expression is altered in several types of human cancers, in mesenchymal cancer cell invasion. Mig-2 is abundantly expressed in SK-LMS-1 leiomyosarcoma cells. The level of Mig-2, however, is considerably lower in more invasive HT-1080 fibrosarcoma cells. Overexpression of Mig-2 in HT-1080 and SK-LMS-1 cells substantially reduced their ability to invade ECM in an in vitro Matrigel invasion assay. Conversely, knockdown of Mig-2 markedly increased the invasiveness of these cells. Consistent with a suppressive role in mesenchymal cancer cell invasion, Mig-2 inhibits urokinase-type plasminogen activator (uPA) secretion and pericellular proteolysis. Overexpression of Mig-2 increased uPA accumulation at the intracellular face of cell-ECM adhesions and reduced the level of secreted uPA. Conversely, knockdown of Mig-2 reduced uPA accumulation at the intracellular face of cell-ECM adhesions and increased uPA secretion. Our results reveal an important role of Mig-2 in suppression of mesenchymal cancer cell invasion and shed new light on how altered Mig-2 expression could influence cancer cell invasion. (Mol Cancer Res 2008;6(5):715 -24)

The kindlin family: functions, signaling properties and implications for human disease

“…Kindlin-2 has also suggested to enhance genome instability, a hallmark of cancer formation, although it is not clear how this is achieved at the molecular level (Zhao et al, 2013). It has also been reported that, in mesenchymal tumor cells, high kindlin-2 levels suppress invasion through inhibition of urokinasetype plasminogen activator (uPA) secretion (Shi and Wu, 2008) and impair tumor progression of serous epithelial ovarian cancer through up-regulation of estrogen receptors, which leads to mesenchymal-toepithelial transition (MET) and, as a consequence, to reduced tumor cell dissemination (Ren et al, 2014).…”

“…Both, talin and kindlins contain a 4.1 protein, ezrin, radixin, moesin (FERM)-like domain, consisting of three subdomains (F1, F2 and F3) (Shi and Wu, 2008;Kloeker et al, 2004). The F3 subdomain harbors a phosphotyrosine-binding (PTB)-fold that can directly bind to the NPxY motifs in β-integrin subunits.…”

“…In contrast to talin, the kindlin FERM domain contains a pleckstrin homology (PH) domain that is inserted in the F2 subdomain (Kloeker et al, 2004;Shi and Wu, 2008 (Qu et al, 2011;Legate et al, 2013), which supports FA targeting, integrin-meditated adhesion and fibronectin deposition (Qu et al, 2011). In contrast to talin, kindlins contain no obvious actin-binding sites; therefore, linkage to actin is mediated through their binding to the ILK-PINCH-parvin (IPP) complex and/or migfilin (also known as FBLIM1) (Mackinnon et al, 2002;Tu et al, 2003).…”

Role of Kindlin-2 in Fibroblast Functions: Implications for Wound Healing

“…However, overexpression and knockdown experiments yielded contradicting results regarding specific functions. Evidence for both suppression of cancer cell invasion in leiomyosarcoma or colon carcinoma cell lines (Shi et al, 2007;Shi and Wu, 2008) and stimulation of cell migration in malignant mesothelioma and in HUVEC cells (Ma et al, 2008;An et al 2010) was found. These observations suggest that the functions of kindlin-2 are cell type-or integrin-specific, and that its role in cell motility may differ depending on the biological context.…”

Cancer cell metastasis; perspectives from the focal adhesion

“…Finally, Mig-2 deregulation [29] could contribute to BC malignancy and progression. Previous work from our research group [16] has actually shown that Mig-2 expression was significantly reduced in human BC tissues compared to normal adjacent tissue indicating that BC has lost Mig-2 expression and thereby has less invasion inhibitory mechanisms in action, as Mig-2 has been implicated in inhibition of cell invasion [30] .…”