Identification of a novel protein, LYRIC, localized to tight junctions of polarized epithelial cells

Brown University, Providence, Rhode Island, United States
Experimental Cell Research (Impact Factor: 3.25). 11/2004; 300(1):134-48. DOI: 10.1016/j.yexcr.2004.06.026
Source: PubMed


Tight junctions (TJ) are multiprotein complexes that function to regulate paracellular transport of molecules through epithelial and endothelial cell layers. Many new tight junction-associated proteins have been identified in the past few years, and their functional roles and interactions have just begun to be elucidated. In this paper, we describe a novel protein LYsine-RIch CEACAM1 co-isolated (LYRIC) that is widely expressed and highly conserved between species. LYRIC has no conserved domains that would indicate function and does not appear to be a member of a larger protein family. Data from analysis of rat and human tissue sections and cell lines show that LYRIC colocalizes with tight junction proteins ZO-1 and occludin in polarized epithelial cells, suggesting that LYRIC is part of the tight junction complex. LYRIC dissociates from ZO-1 when junctional complexes are disrupted, and as tight junctions reform, ZO-1 relocalizes before LYRIC. These results suggest that LYRIC is most likely not a structural component required for TJ formation, but rather is recruited during the maturation of the tight junction complex.

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    • "Another report by Huang et al. demonstrated that the metastatic abilities of nasopharyngeal carcinoma were associated with phosphorylation of lysine-rich CEACAM1 co-isolated protein (LYRIC) [41]. Indeed, LYRIC is described to be a part of the tight junction complex [42]. Since tight junctions create an intercellular barrier and an intramembrane diffusion fence, reduction of these junctions due to LYRIC phosphorylation can initiate metastatic processes [43]. "

    Full-text · Article · Jul 2015
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    • "Next, Brown and Ruoslahti (10) used a phage expression library of complementary deoxyribonucleic acid (cDNA) from a mouse model of the lung metastasis of breast carcinoma to identify a lung homing peptide in AEG-1/MTDH that was overexpressed in metastatic breast cancer and promoted the homing of breast cancer cells to the lungs. In 2004, Britt et al (11) and Sutherland et al (12) separately reported a novel protein, LYRIC, that colocalized with the tight junction protein, ZO-1, in polarized prostate epithelial cells (11) and was present in the cytoplasm, endoplasmic reticulum (ER), perinuclear regions and nucleolus (12). "
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    ABSTRACT: Tumor development is initiated by an accumulation of numerous genetic and epigenetic alterations that promote tumor initiation, invasion and metastasis. Astrocyte elevated gene-1 [AEG-1; also known as Metadherin (MTDH) and Lysine-rich CEACAM1 co-isolated (LYRIC)] has emerged in recent years as a potentially crucial mediator of tumor malignancy, and a key converging point of a complex network of oncogenic signaling pathways. AEG-1/MTDH has a multifunctional role in tumor development that has been found to be involved in the following signaling cascades: i) The Ha-Ras and PI3K/Akt pathways; ii) the nuclear factor-κB signaling pathway; iii) the ERK/mitogen-activated protein kinase and Wnt/β-catenin pathways; and iv) the Aurora-A kinase signaling pathway. Studies have established that AEG-1/MTDH is crucial in tumor progression, including transformation, the evasion of apoptosis, invasion, angiogenesis and metastasis. In addition, recent clinical studies have convincingly associated AEG-1/MTDH with tumor progression and poor prognosis in a number of cancer types, including hepatocellular, esophageal squamous cell, gallbladder and renal cell carcinomas, breast, non-small cell lung, prostate, gastric and colorectal cancers, and glioma, melanoma, neuroblastoma and osteosarcoma. AEG-1/MTDH may be used as a biomarker to identify subgroups of patients who require more intensive treatments and who are likely to benefit from AEG-1/MTDH-targeted therapies. The therapeutic targeting of AEG-1/MTDH may simultaneously block metastasis, suppress tumor growth and enhance the efficacy of chemotherapeutic treatments.
    Full-text · Article · Aug 2014 · Oncology letters
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    • "Numerous studies have validated that anoikis can be inhibited when cell-cell adhesion is preserved in various epithelial carcinoma cell lines [60]–[61]. The mouse/rat orthologue of AEG-1 was found to encode the lysine-rich CEACAM-1 co-isolated protein (Lyric) that co-localizes with the tight junction protein ZO-1 in polarized rat prostate epithelial cells [62]. AEG-1 also has been suggested to regulate the expressions of β-catenin [16], ICAM2, ICAM3, selectin E and selectin P [63], all of which are associated with the cell-extracellular matrix or cell-cell adhesion. "
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    ABSTRACT: Metastasis contributes to the poor prognosis of hepatocellular carcinoma (HCC). Anoikis resistance and orientation chemotaxis are two important and sequential events in tumor cell metastasis. The process of tumor metastasis is known to be regulated by AEG-1, an important oncogene that plays a critical role in tumor metastasis, though the effects of this oncogene on anoikis resistance and orientation chemotaxis in HCC cells are currently unknown. To directly assess the role of AEG-1 in these processes, we up-regulated AEG-1 expression via exogenous transfection in SMMC-7721 cells, which express low endogenous levels of AEG-1; and down-regulated AEG-1 expression via siRNA-mediated knockdown in MHCC-97H and HCC-LM3 cells, which express high endogenous levels of AEG-1. Our data directly demonstrate that AEG-1 promotes cell growth as assessed by cell proliferation/viability and cell cycle analysis. Furthermore, the prevention of anoikis by AEG-1 correlates with decreased activation of caspase-3. AEG-1-dependent anoikis resistance is activated via the PI3K/Akt pathway and is characterized by the regulation of Bcl-2 and Bad. The PI3K inhibitor LY294002 reverses the AEG-1 dependent effects on Akt phosphorylation, Bcl-2 expression and anoikis resistance. AEG-1 also promotes orientation chemotaxis of suspension-cultured cells towards supernatant from Human Pulmonary Microvascular Endothelial Cells (HPMECs). Our results show that AEG-1 activates the expression of the metastasis-associated chemokine receptor CXCR4, and that its ligand, CXCL12, is secreted by HPMECs. Furthermore, the CXCR4 antoagonist AMD3100 decreases AEG-1-induced orientation chemotaxis. These results define a pathway by which AEG-1 regulates anoikis resistance and orientation chemotaxis during HCC cell metastasis.
    Full-text · Article · Jun 2014 · PLoS ONE
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