Abstract
The ability of integrins on the cell surface to mediate cell adhesion to the extracellular matrix ligands is regulated by intracellular signaling cascades. During this signaling process, the talin (TLN) recruited to integrin cytoplasmic tails plays the critical role of the major adaptor protein to trigger integrin activation. Thus, intracellular levels of TLN are thought to determine integrin-mediated cellular functions. However, the epigenetic regulation of TLN expression and consequent modulation of integrin activation remain to be elucidated. Bioinformatics analysis led us to consider miR-200c-3p as a TLN1-targeting miRNA. To test this, we have generated miR-200c-3p-overexpressing and miR-200c-3p-underexpressing cell lines, including HEK293T, HCT116, and LNCaP cells. Overexpression of miR-200c-3p resulted in a remarkable decrease in the expression of TLN1, which was associated with the suppression of integrin-mediated cell adhesion to fibronectin. In contrast, the reduction in endogenous miR-200c-3p levels led to increased expression of TLN1 and enhanced cell adhesion to fibronectin and focal adhesion plaques formation. Moreover, miR-200c-3p was found to target TLN1 by binding to its 3′-untranslated region (UTR). Taken together, our data indicate that miR-200c-3p contributes to the regulation of integrin activation and cell adhesion via the targeting of TLN1.
Highlights
The ability of integrins on the cell surface to mediate cell adhesion to the extracellular matrix ligands is regulated by intracellular signaling cascades
A proper balance in the activation and deactivation of integrins is critical for up- and down-regulating cell adhesion to extracellular matrix (ECM), which constitute some of the basic steps for various biological and pathological p rocesses[41,42]
Integrin activation is achieved by inside-out and intracellular signaling that culminates in the association of multiple adaptor proteins to integrin cytoplasmic tails
Summary
The ability of integrins on the cell surface to mediate cell adhesion to the extracellular matrix ligands is regulated by intracellular signaling cascades. For the most part, coordinates the assembly of multiprotein adhesion complexes that mediate biological processes such as cell migration and, more complex phenomena including embryogenesis and tumorigenesis[6] To facilitate these assemblages, talin initially forms a nascent complex through its intracellular interaction with the transmembrane receptor, integrin[12], and the cytoskeletal protein, a ctin[13]. The importance of talin in orchestrating these multiprotein assemblages and impacting several important biological processes has been highlighted in studies with mice whose TLN genes were a blated[9,11] Deletion of both TLN1 and TLN2 in cardiomyocytes has resulted in heart failure and death, possibly due to the decrease in expression and function of costameric proteins, notably integrin β1D9. Our study suggests that cellular levels of miR-200c-3p govern integrinmediated cell adhesion via targeting TLN1
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