Function
Cingulin is specifically localized at tight junctions in epithelial cells, unlike ZO-1, which is also detected at adherens-type junctions in non-epithelial cells. During early Xenopus embryo development, cingulin is detected at a cortical localization, and then accumulates at apical junctions, unlike ZO-1 and other junctional proteins, that are targeted to the new regions of cell-cell contact via the lateral domain. Cingulin interacts with ZO-1 and several other tight junction proteins, in addition to interacting with actin and myosin. A conserved sequence in the N-terminal region of cingulin is required for junctional recruitment and interaction with ZO-1. The notion that that ZO-1 recruits cingulin to tight junctions is confirmed by the observation that epithelial cells lacking ZO-1 lose cingulin junctional staining.
The function of cingulin has been studied by knockout and knockdown approaches. Embryoid bodies derived from embryonic stem cells where one or both cingulin alleles were targeted by homologous recombination show apparently normal tight junctions, but changes in the expression of a large number of genes, including tight junction protein genes (claudin-2, claudin-6, claudin-7 and occludin) and transcription factors (GATA4). Changes in the expression of claudin-2 and ZO-3 are also observed in cultured kidney cells (MDCK) depleted of cingulin by shRNA. These effects of cingulin depletion on gene expression are thought to be mediated at least in part by the regulation of RhoA activity by cingulin, since they can be reversed by dominant-negative RhoA. Indeed, cingulin interacts with the RhoA exchange factor GEF-H1, and inactivates it by recruiting it to junctions when cells reach confluence. It was therefore hypothesized that the accumulation of cingulin at mature junctions of confluent monolayers is one mechanism to down-regulate RhoA activity once cells reach confluence. Cells depleted of cingulin also show increased density and proliferation, indicating that cingulin contributes to regulating cell proliferation. Cingulin is also implicated in the junctional recruitment of the RhoGEF p114RhoGEF, which activates RhoA at tight junctions and is required for junction assembly (Terry et al., Nat. Cell Biol. 2011). Cingulin is expressed in some but not all human carcinomas, for example its expression is strongly downregulated in epidermoid carcinomas of the lung. Histone deacetylase inhibitors such as sodium butyrate strongly up-regulate cingulin expression in some cultured cells, indicating that cingulin is a marker of epithelial differentiation.
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