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  • Furthermore a study in Drosophila

    2024-07-10

    Furthermore, a study in Drosophila has reported that Dpatj can interact directly with Dmpar6 providing another potential mechanism linking the Crb to the Par complex [163]. In contrast, Wang et al. in 2004 [63] have shown that at least in MDCK epithelial cells, PAR6 binding to PALS1 interferes with PATJ binding to PALS1, and that these interactions do not work synergistically. The CRB-conserved ERLI motif may therefore link CRB to the PAR complex via multiple mechanisms. In addition to interact with each others, these three complexes have been found to interact with cytoskeleton-related proteins, such as 14.3.3 protein for PAR complex [75], YMO1 (yurt/mosaic eyes like 1) protein for CRB complex [164] and Myosin II for SCRIB complex [165]. These interactions modulate the dynamic of Diclazuril cytoskeleton, one of the key events controlling cell shape and polarity.
    Conclusion and perspectives Although polarity complexes are involved in the formation and maintenance of tight junctions in mammalian epithelial cells, the exact mechanisms underlying their role are not yet understood. In addition, these polarity complexes have been found to be involved in other cellular events such as gene expression, differentiation, motility and growth by the identification of new molecular interactions (Fig. 2). Recently, new interactors have been identified like EHM2 (expressed in high-metastatic cell) and YMO1, which is also known as EPB41L5 (erythrocyte protein band 4.1-like 5), which interact in a FERM domain-dependent manner with CRB1, CRB2 and CRB3 [164]. Their Drosophila homologue (Yurt) acts as a negative regulator of Crb activity both in epithelial polarity processes and at the apical membrane surface via a mechanism that is not yet fully understood [164]. Wang et al. [110] recently reported that PALS1 is involved in the regulation of E-cadherin trafficking. E-cadherin accumulates in intracellular structures inside PALS1 knock down cells, which indicates that the CRB complex might regulate the recycling of adhesion molecules. The existence of link between the CRB complex and vesicular trafficking agrees with the finding that PATJ and MUPP1 bind to Angiomotin (Amot) [166], which is required (along with Rich1, a Cdc42-GAP) for the targeting of PALS1 and PAR3 to the plasma membrane [167]. Moreover in Drosophila, proteins involved in membrane recycling such as Avalanche and Rab5 also contribute importantly to the proper localization and functional integrity of the Crb complex [168]. The occurrence of 10 and 13 PDZ domains in PATJ and MUPP1, respectively, might indicate that many proteins other than Claudins and JAM can be tethered to the tight junction via MUPP1 and PATJ molecules. MUPP1 certainly interacts via these domains with several molecules (Fig. 1, Fig. 2), including the proto-oncogene c-Kit [169], the transmembrane proteoglycan NG2 [170], an adenovirus E4-ORF1 oncoprotein [171], and Amot [166], which suggests the possible involvement of MUPP1 and PATJ in growth, proliferation and cell movement. This hypothesis is in line with a recent interaction found to occur between PATJ and the tuberous sclerosis complex 2 (TSC2 or Tuberin) protein [172]. TSC2 associated to TSC1 (Hamartin) forms a complex that regulates the mTOR cascade through the GAP activity of TSC2 on Rheb, a small GTP-binding protein [173]. PATJ binds to the last amino acids of TSC2 via its PDZ domains 2 and 3, and depletion of PATJ from human epithelial intestinal cells induced an upregulation of the mTOR pathway, indicating that the CRB3 complex is able to regulate the activity of TSC on the mTOR cascade [172]. This finding opens new paths for understanding the role of the CRB complex in the regulation of cell metabolism, size and survival. SCRIB has been found to be involved in the recycling and signaling of transmembrane receptor TSHR (thyroid stimulating hormone receptor) via the ╬▓PIX/GIT1/ARF6 pathway [174]. The interactions occurring between SCRIB and members of the Zyxin family (TRIP6 and LPP) have also suggested the existence of a new communication pathway between cell contact and the nucleus [175], [176].