Tight Junction Signaling


Pathway Description

Tight Junctions comprise at least four types of transmembrane proteins, including occludins, claudins, JAMs and Crb, and a number of cytoplasmic peripheral proteins. Tight Junctions are located at the uppermost portion of the lateral plasma membrane, where claudins appear to be involved in the homophilic and/or heterophilic interactions implicated in firm adhesions. Tight Junction strands are linear co-polymers of occludin, claudins and JAMs. PATJ interacts with PALS1, Crb1 and Crb3 to form a tripartite tight junction complex involved in epithelial cell polarity.It is most likely that aPKC binds to PALS1-PATJ-Crb, and phosphorylates Crb. aPKC also associates with the PAR3-PAR6 polarity complex that is recruited to tight junctions. PAR-3 and PAR-6 interact with Crb and PALS1 complex and promote tight junction assembly and apicobasal polarity. The interaction between PAR-6 and PALS1 is regulated by CDC42. PAR-6 interaction with GTP-bound CDC42, a key modulator of the Actin cytoskeleton, results in the activation of aPKC at sites of cell-cell junctions. CDC42 binding to PAR-6 links the tight junction protein complexes to a signaling pathway regulating cytoskeleton and tight junction assembly. Furthermore, aPKC, PAR-6 and mLGL form another multi-protein complex in which mLGL is phosphorylated by aPKC. mLGL phosphorylation is required for its interaction with Stx4 and for regulation of protein trafficking. aPKC function is inhibited by PP2A.

Unlike claudin, occludin is likely to be involved in establishing the seal at the sites of junctional strands. ZO2 recruits aPKC, Rab13, PKA and other Rab GTPases to facilitate vesicular trafficking and to recruit claudin1 and ZO1 to tight junctions. Both PKA and aPKC control vesicle-mediated transport steps. Rab13 interacts directly with PKA and inhibits PKA-dependent phosphorylation of VASP that is essential for actin remodeling. The cAMP/PKA/Rab GTPase activity stimulates apically-directed transcytosis.

TNF-α activates Itg-ILK/-GSK3-p130Cas-JNK signaling and perturbs the stability of the tight junction barrier. Increase in PTEN activity suppresses the Itg-ILK-GSK3-p130Cas-JNK signaling by decreasing Akt-induced GSK3 activation, and this alters occludin levels near tight junctions. Similarly, TGF-β regulates junction dynamics by promoting PAR-3 induced cell adhesion near occludin and JAM junctions.

The components of the PAR-3/PAR-6/aPKC complex near JAMs regulate several signaling mechanisms that control epithelial polarization. PAR-3 regulates tight junction assembly through a PAR-6/aPKC-independent mechanism by regulating Rac1 activation via TIAM1 to formulate F-actin/myosin binding and cell adhesion. aPKC and CDC42 regulate vesicular trafficking, organization of the microtubule network and polarized membrane traffic. Apart from other cell adhesion regulators like ZO1, ZONAB, protein 4.1, afadin, spectrin/fodrin, PILT, Cgn, CASK, MAGI1, α-actinin, F-actin and myosin also form plaques near the cytoplasmic domains of JAMs to promote firm adhesions. RhoA signaling regulates actin-based motility in high-density epithelial cells by inhibiting GEFH1, and this influences cell migration and cell cycle progression. By contrast, PAR-6 is also linked to the loss of the epithelial phenotype; TGF-β-induced epithelial-mesenchymal transition requires PAR-6 phosphorylation by TGF-βR. Cytoplasmic sequestration of ZONAB/CDK4 results in co-regulation of 2 different mechanisms that affect G1/S phase transition. ZO2 interacts with ZO1, enters the nucleus and binds with the hnRNP, SAFB to inhibit the transcription factors AP-1 and CEBP, resulting in deregulation of cell proliferation and differentiation.