Cingulin, paracingulin, and PLEKHA7: signaling and cytoskeletal adaptors at the apical junctional complex

Abstract

Cingulin, paracingulin, and PLEKHA7 are proteins localized in the cytoplasmic region of the apical junctional complex of vertebrate epithelial cells. Cingulin has been detected at tight junctions (TJs), whereas paracingulin has been detected at both TJs and adherens junctions (AJs) and PLEKHA7 has been detected at AJs. One function of cingulin and paracingulin is to regulate the activity of Rho family GTPases at junctions through their direct interaction with guanidine exchange factors of RhoA and Rac1. Cingulin also contributes to the regulation of transcription of several genes in different types of cultured cells, in part through its ability to modulate RhoA activity. PLEKHA7, together with paracingulin, is part of a protein complex that links E-cadherin to the microtubule cytoskeleton at AJs. In this paper, we review the current knowledge about these proteins, including their discovery, the characterization of their expression, localization, structure, molecular interactions, and their roles in different developmental and disease model systems.

The N and C Termini of ZO-1 Are Surrounded by Distinct Proteins and Functional Protein Networks

“…4, fourth row, right) (43), cingulin (fifth row, left), Lim domain only protein 7 (LMO7) (fifth row, middle), and cytoplasmic actin (ACTB) (fifth row, right). Consistent with this differential tagging, cingulin (22) and actin (21) are known to interact with the C terminus of ZO-1. LMO7 is known to interact at cell junctions with nectin and afadin and to shuttle to the nucleus, where it functions as a transcriptional regulator (44).…”

“…The guanylate kinase domain is the binding site for occludin (19,20). The C-terminal end of ZO-1 contains an actin filament binding site (21) and interacts with the signaling and cytoskeletal adaptor protein, cingulin (22). Because these and other unique protein-protein interactions have already been defined for the N-and C-terminal halves of ZO-1, we separately fused biotin ligase to each end of ZO-1 to ask whether the radius of activity of the fused ligase (12) was sufficiently limited to allow selective tagging of proteins proximal to each end.…”

The adherens junctions control susceptibility to Staphylococcus aureus α-toxin

“…PLEKHA7 localizes to the zonula adhaerens belt of the apical-junctional complex in epithelial cells, where it directly interacts with p120 catenin, paracingulin, and afadin (24,(28)(29)(30)(31). Unlike E-cadherin or p120 catenin, PLEKHA7 is not required for adherens junctions formation, and previous studies suggest a role for PLEKHA7 in regulating the stability of the adherens junctions (24,(28)(29)(30)(31). In accord with adherens junctions mediating α-toxin injury, our screen also identified several other junctional components including α-catenin, afadin, and Fig.…”

“…PLEKHA7 is known to link microtubules to the adherens junctions and regulate stability of the junctions (24,30), which may serve to coordinate these hypothesized functions. Our data support a new biological role for intracellular components of the adherens junctions in regulating cellular injury in response to α-toxin, a paradigm that warrants future investigation.…”

PLEKHA7 Recruits PDZD11 to Adherens Junctions to Stabilize Nectins

“…PLEKHA7 is a recently discovered cytoplasmic component of AJ, which was identified through its interaction with the AJ protein p120-catenin (6) and with the TJ/AJ protein paracingulin (CGNL1) (7)(8)(9). PLEKHA7 is specifically associated with the zonula adhaerens (ZA) (7), and it interacts with the microtubule-interacting protein nezha (CAMSAP3) to provide a molecular linkage between the cadherin-associated protein complex and the microtubule cytoskeleton (6).…”