Cadmium affects focal adhesion kinase (FAK) in mesangial cells: Involvement of CaMK‐II and the actin cytoskeleton

Abstract

The toxic metal ion cadmium (Cd(2+)) induces pleiotropic effects on cell death and survival, in part through effects on cell signaling mechanisms and cytoskeletal dynamics. Linking these phenomena appears to be calmodulin-dependent activation of the Ca(2+)/calmodulin-dependent protein kinase II (CaMK-II). Here we show that interference with the dynamics of the filamentous actin cytoskeleton, either by stabilization or destabilization, results in disruption of focal adhesions at the ends of organized actin structures, and in particular the loss of vinculin and focal adhesion kinase (FAK) from the contacts is a result. Low-level exposure of renal mesangial cells to CdCl2 disrupts the actin cytoskeleton and recapitulates the effects of manipulation of cytoskeletal dynamics with biological agents. Specifically, Cd(2+) treatment causes loss of vinculin and FAK from focal contacts, concomitant with cytoskeletal disruption, and preservation of cytoskeletal integrity with either a calmodulin antagonist or a CaMK-II inhibitor abrogates these effects of Cd(2+). Notably, inhibition of CaMK-II decreases the migration of FAK-phosphoTyr925 to a membrane-associated compartment where it is otherwise sequestered from focal adhesions in a Cd(2+)-dependent manner. These results add further insight into the mechanism of the CaMK-II-dependent effects of Cd(2+) on cellular function.

Cadmium stimulates metastasis-associated phenotype in triple-negative breast cancer cells through integrin and β-catenin signaling

“…2). In this study, it was found that Cd, instead of disrupting focal adhesion as reported by Choong et al (2013), induced phosphorylation of focal adhesion kinases in breast cancer cells. This is a significant finding, because metastatic colonization at distant sites requires activation of integrin- mediated signaling (Reticker-Flynn et al, 2012).…”

“…Exposure to Cd leads to disassembly of microtubules in mouse 3T3 cells (Perrino and Chou, 1986). In Cd-treated mouse mesangial cells, actin filaments become irregular and are lost because of disturbances in focal adhesion (Choong et al, 2013). In contrast to these findings of cytoskeleton disruption upon Cd treatment, the results of the present study show that Cd treatment increases α-actinin, a binder of actin filaments polymerization, indicating active cytoskeleton buildup in the MDA-MB-231 cells (Fig.…”

European sea bass gill pathology after exposure to cadmium and terbuthylazine: expert versus fractal analysis

“…Moreover cadmium has been shown to interfere with the integrity of the actin cytoskeleton and the function of the cadherin cell–cell adhesion molecules (Prozialeck & Edwards, ; Choong et al ., ). Cadmium exposure has also been shown to disrupt vinculin‐ and focal adhesion kinase‐rich focal contacts through a Ca 2+ /calmodulin‐dependent protein kinase II (CaMK‐II) pathway cell (Choong et al ., ). Physical disruption of cell–cell and cell–matrix adhesions might well explain the cell coarctation and curling observed in this study.…”

Ninjurin1 inhibits colitis-mediated colon cancer development and growth by suppression of macrophage infiltration through repression of FAK signaling

“…Loss of tyrosine phosphorylation of FAK is associated with disruption of focal adhesions and acquisition of a motile phenotype [ 30 ]. FAK may also promote cell migration by influencing the remodeling of the actin cytoskeleton [ 31 ]. Our data revealed that ninjurin1 overexpression suppresses FAK activation and actin clustering at the cell leading edge.…”