Dual Function of Par3 in Tumorigenesis

Abstract

Cell maintenance and the establishment of cell polarity involve complicated interactions among multiple protein complexes as well as the regulation of different signaling pathways. As an important cell polarity protein, Par3 is evolutionarily conserved and involved in tight junction formation as well as tumorigenesis. In this review, we aimed to explore the function of Par3 in tumorigenesis. Research has shown that Par3 exhibits dual functions in human cancers, both tumor-promoting and tumor-suppressive. Here, we focus on the activities of Par3 in different stages and types of tumors, aiming to offer a new perspective on the molecular mechanisms that regulate the functions of Par3 in tumor development. Tumor origin, tumor microenvironment, tumor type, cell density, cell-cell contact, and the synergistic effect of Par3 and other tumor-associated signaling pathways may be important reasons for the dual function of Par3. The important role of Par3 in mammalian tumorigenesis and potential signaling pathways is context dependent.

Keywords: Par3; cell polarity; dual function; tumor-promoting; tumor-suppressive.

Figure 1

Two dimensional (2D) and partial three-dimensional (3D) structures of Par3. (A) Par3 encodes a protein of 1,356 amino acids, consisting of an N-terminal domain, a C-terminal domain, and three PDZ domains, namely, PDZ1, PDZ2, and PDZ3. The interacting proteins of Par3 are indicated above the approximate localization of the binding sites. (B) A ribbon diagram of the crystal structure of the two Par-3 NTD molecules in the asymmetric unit (PDB accession number:416P). The two molecules, colored green and brown, respectively, are arranged in a ‘‘front-to-back’’ manner. (C) A ribbon diagram of the Par3 PDZ2 domain structure (PDB accession number:2KOM). (D) A ribbon representation of the Par3 PDZ3 domain (PDB accession number:6JUE).

Figure 2

The function of Par3 in tumor promotion. The activation of Rac1 is mediated by Par3/aPKCλ, which is necessary to promote the activation of Stat3. Par3 interacts with PP1A and the Hippo pathway kinase Lats1 to induce its dephosphorylation and thereby lead to the activation of TAZ in the cytoplasm. Par3 also sequesters Kibra to form a Par3/aPKC/Kibra complex, leading to the dissociation of the canonical Kibra/Merlin/FRMD6 complex and a decrease in the phosphorylation of Lats, resulting in the dephosphorylation of Yap for cytoplasmic arrest.

Figure 3

The function of Par3 in tumor suppression. The loss of Par3 in tumor cells is related to the abnormal expression of some important genes, such as P-cadherin, Snail1, and MMP9, and the abnormal regulation of some signaling pathways, such as the Stat3, Tiam1/Rac1, and Notch signaling pathways. The loss of Par3 also leads to the dissociation of the Par3/Merlin/Lats1 complex, leading to decreased Hippo pathway signaling and enhanced nuclear translocation of Yap, resulting in the transcriptional activation of Ki-67 and Sox2. The phosphorylation of Par-6, which is regulated by TGF-β1, can recruit the ubiquitin ligase Smurf1 to the receptor and lead to the localized degradation of RhoA GTPase, thereby leading to the disruption of the tight junction.

Figure 4

Dual function model of Par3. The expression of Par3 is rarely observed at cell–cell contact sites during keratoacanthoma formation, while robust expression and localization of Par3 are strongly correlated with papilloma formation. Tiam1/Rac signaling can regulate the Par3 complex in keratinocytes, while the inhibitory function of Par3 on keratoacanthoma formation is not observed in Tiam1- and Rac1-deficient mice, indicating that Tiam/Rac signaling is crucial for Par3 function as a tumor repressor. A Par3–YAP complex is reported to regulate the Hippo–YAP pathway in a manner dependent on cell density and cell–cell contact. The dual function of Par3 is related to its synergistic effects with other oncogenes, such as Ras and ErbB2.