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Frank Thevenod - One of the best experts on this subject based on the ideXlab platform.
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tonicity inversely modulates lipocalin 2 LCN2 24p3 ngal receptor slc22a17 and LCN2 expression via wnt β catenin signaling in renal inner medullary collecting duct cells implications for cell fate and bacterial infection
Cell Communication and Signaling, 2018Co-Authors: R Betten, Bettina Scharner, Bayram Edemir, Christian Langelueddecke, Natascha A Wolff, S. Probst, Frank ThevenodAbstract:We have previously evidenced apical expression of the 24p3/NGAL/lipocalin-2 receptor (LCN2-R; SLC22A17) in inner medullary collecting duct (IMCD) cells, which are present in vivo in a hyperosmotic/-tonic environment that activates canonical Wnt/β-catenin signaling. The localization of LCN2-R in the inner medulla is intriguing considering local bacterial infections trigger toll-like receptor-4 (TLR-4)-mediated secretion of the bacteriostatic Fe3+-free (apo-)LCN2. To determine the effects of osmolarity/tonicity changes, Wnt/β-catenin and TLR-4 activation on LCN2-R and LCN2 expression and cell viability in rat primary IMCD and mouse (m)IMCD3 cells. Normosmolarity/-tonicity was 300 mosmol/l whereas hyperosmolarity/-tonicity was induced by adding 100 mmol/l NaCl + 100 mmol/l urea (600 mosmol/l, 1-7 days). LCN2-R and LCN2 expression were determined by qPCR, immunoblotting, flow cytometry and immunofluorescence microscopy. β-catenin was silenced by RNAi. Cell viability/death was determined with MTT and LDH release assays. TLR-4 was activated by bacterial lipopolysaccharides (LPS). Hyperosmotic/-tonic media upregulated LCN2-R by ~4-fold and decreased LCN2 expression/secretion, along with Wnt/β-catenin activation, in IMCD cells. These effects of hyperosmotic/-tonic media on LCN2-R/LCN2 expression were reverted by normosmolarity/-tonicity, β-catenin silencing and/or LPS. Exposure of cells with endogenous or stably overexpressing LCN2-R to apo-LCN2 or LPS decreased cell viability. LCN2-R upregulation and LCN2 downregulation via Wnt/β-catenin may promote adaptive osmotolerant survival of IMCD cells in response to hyperosmolarity/-tonicity whereas LCN2 upregulation and LCN2-R downregulation via TLR-4 and/or normosmolarity/-tonicity may protect IMCD cells against bacterial infections and prevent autocrine death induction by LCN2.
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Tonicity inversely modulates lipocalin-2 (LCN2/24p3/NGAL) receptor (SLC22A17) and LCN2 expression via Wnt/β-catenin signaling in renal inner medullary collecting duct cells: implications for cell fate and bacterial infection.
Cell communication and signaling : CCS, 2018Co-Authors: R Betten, Bettina Scharner, Bayram Edemir, Christian Langelueddecke, Natascha A Wolff, S. Probst, Wing-kee Lee, Frank ThevenodAbstract:We have previously evidenced apical expression of the 24p3/NGAL/lipocalin-2 receptor (LCN2-R; SLC22A17) in inner medullary collecting duct (IMCD) cells, which are present in vivo in a hyperosmotic/-tonic environment that activates canonical Wnt/β-catenin signaling. The localization of LCN2-R in the inner medulla is intriguing considering local bacterial infections trigger toll-like receptor-4 (TLR-4)-mediated secretion of the bacteriostatic Fe3+-free (apo-)LCN2. To determine the effects of osmolarity/tonicity changes, Wnt/β-catenin and TLR-4 activation on LCN2-R and LCN2 expression and cell viability in rat primary IMCD and mouse (m)IMCD3 cells. Normosmolarity/-tonicity was 300 mosmol/l whereas hyperosmolarity/-tonicity was induced by adding 100 mmol/l NaCl + 100 mmol/l urea (600 mosmol/l, 1-7 days). LCN2-R and LCN2 expression were determined by qPCR, immunoblotting, flow cytometry and immunofluorescence microscopy. β-catenin was silenced by RNAi. Cell viability/death was determined with MTT and LDH release assays. TLR-4 was activated by bacterial lipopolysaccharides (LPS). Hyperosmotic/-tonic media upregulated LCN2-R by ~4-fold and decreased LCN2 expression/secretion, along with Wnt/β-catenin activation, in IMCD cells. These effects of hyperosmotic/-tonic media on LCN2-R/LCN2 expression were reverted by normosmolarity/-tonicity, β-catenin silencing and/or LPS. Exposure of cells with endogenous or stably overexpressing LCN2-R to apo-LCN2 or LPS decreased cell viability. LCN2-R upregulation and LCN2 downregulation via Wnt/β-catenin may promote adaptive osmotolerant survival of IMCD cells in response to hyperosmolarity/-tonicity whereas LCN2 upregulation and LCN2-R downregulation via TLR-4 and/or normosmolarity/-tonicity may protect IMCD cells against bacterial infections and prevent autocrine death induction by LCN2.
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biochemical and structural characterization of the interaction between the siderocalin ngal LCN2 neutrophil gelatinase associated lipocalin lipocalin 2 and the n terminal domain of its endocytic receptor slc22a17
Journal of Biological Chemistry, 2016Co-Authors: Ana-isabel Cabedo Martinez, Natascha A Wolff, Wing-kee Lee, Katharina Weinhäupl, Barbara Storch, Robert Konrat, Wiktor Koźmiński, Kathrin Breuker, Szymon żerko, Frank ThevenodAbstract:The neutrophil gelatinase-associated lipocalin (NGAL, also known as LCN2) and its cellular receptor (LCN2-R, SLC22A17) are involved in many physiological and pathological processes such as cell differentiation, apoptosis, and inflammation. These pleiotropic functions mainly rely on NGAL's siderophore-mediated iron transport properties. However, the molecular determinants underlying the interaction between NGAL and its cellular receptor remain largely unknown. Here, using solution-state biomolecular NMR in conjunction with other biophysical methods, we show that the N-terminal domain of LCN2-R is a soluble extracellular domain that is intrinsically disordered and interacts with NGAL preferentially in its apo state to form a fuzzy complex. The relatively weak affinity (≈10 μm) between human LCN2-R-NTD and apoNGAL suggests that the N terminus on its own cannot account for the internalization of NGAL by LCN2-R. However, human LCN2-R-NTD could be involved in the fine-tuning of the interaction between NGAL and its cellular receptor or in a biochemical mechanism allowing the receptor to discriminate between apo- and holo-NGAL.
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Biochemical and Structural Characterization of the Interaction between the Siderocalin NGAL/LCN2 (Neutrophil Gelatinase-associated Lipocalin/Lipocalin 2) and the N-terminal Domain of Its Endocytic Receptor SLC22A17.
The Journal of biological chemistry, 2015Co-Authors: Ana-isabel Cabedo Martinez, Natascha A Wolff, Wing-kee Lee, Katharina Weinhäupl, Barbara Storch, Szymon Żerko, Robert Konrat, Wiktor Koźmiński, Kathrin Breuker, Frank ThevenodAbstract:The neutrophil gelatinase-associated lipocalin (NGAL, also known as LCN2) and its cellular receptor (LCN2-R, SLC22A17) are involved in many physiological and pathological processes such as cell differentiation, apoptosis, and inflammation. These pleiotropic functions mainly rely on NGAL's siderophore-mediated iron transport properties. However, the molecular determinants underlying the interaction between NGAL and its cellular receptor remain largely unknown. Here, using solution-state biomolecular NMR in conjunction with other biophysical methods, we show that the N-terminal domain of LCN2-R is a soluble extracellular domain that is intrinsically disordered and interacts with NGAL preferentially in its apo state to form a fuzzy complex. The relatively weak affinity (≈10 μm) between human LCN2-R-NTD and apoNGAL suggests that the N terminus on its own cannot account for the internalization of NGAL by LCN2-R. However, human LCN2-R-NTD could be involved in the fine-tuning of the interaction between NGAL and its cellular receptor or in a biochemical mechanism allowing the receptor to discriminate between apo- and holo-NGAL.
Shao-hong Wang - One of the best experts on this subject based on the ideXlab platform.
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LCN2-interacting proteins and their expression patterns in brain tumors
Brain research, 2019Co-Authors: Qiaoxi Xia, Yan Zhao, Ling Lin, Zhixiong Cai, Shao-hong WangAbstract:Lipocalin 2 (LCN2) is a member of the lipocalin family. Elevated expression of LCN2 has been observed in many human tumors, suggesting it might be a potential biomarker and/or therapeutic target in malignancies. In this study, we aimed to explore LCN2 interacting proteins through bioinformatics, as well as their biological functions. Protein-protein interaction networks (PPIN) were constructed using LCN2 and its interacting proteins as the core node. These PPINs were scale free biological networks in which LCN2 and its interacting proteins could connect or cross-talk with at least one partner protein. Both functional and KEGG pathway enrichment analyses identified the known and potential biological functions of the PPIN, such as cell migration and cancer-related pathways. Expression levels of the PPIN proteins, as well as their expression correlations, in five types of brain tumor, were analyzed and integrated into the PPIN to illustrate a dynamic change. A significant correlation was found between the survival time of glioblastoma patients and the expression level of 10 genes (LCN2, MMP9, MMP2, PDE4DIP, L2HGDH, HNRNPA1, DDX31, LOXL2, FAM60A and RNF25). Taken together, our results suggest that LCN2 and its interacting proteins are mostly differentially expressed and have a distinguishing co-expression pattern. They might promote proliferation and migration via cell migration signaling and cancer-related pathways. LCN2 and its interacting proteins might be potential biomarkers in glioblastoma.
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tcf7l2 and egr1 synergistic activation of transcription of LCN2 via an erk1 2 dependent pathway in esophageal squamous cell carcinoma cells
Cellular Signalling, 2019Co-Authors: Yan Zhao, Qiaoxi Xia, Yan Liu, Wen-jing Bai, Yubin Yao, Jiyu Ding, Ling Lin, Zhixiong Cai, Shao-hong WangAbstract:Abstract High level expression of lipocalin 2 (LCN2) usually indicates poor prognosis in esophageal squamous cell carcinoma (ESCC) and many other cancers. Our previous study showed LCN2 promotes migration and invasion of ESCC cells through a novel positive feedback loop. However, the key transcription activation protein (KTAP) in the loop had not yet been identified. In this study, we first predicted the most probable KTAPs by bioinformatic analysis. We then assessed the transcription regulatory regions in the human LCN2 gene by fusing deletions of its 5′-flanking region to a dual-luciferase reporter. We found that the region −720/−200 containing transcription factor 7-like 2 (TCF7L2) (−273/−209) and early growth response 1 (EGR1) (−710/−616) binding sites is crucial for LCN2 promoter activity. Chromatin immunoprecipitation (ChIP) experiments demonstrated that TCF7L2 and EGR1 bound directly to their binding sites within the LCN2 promoter as KTAPs. Mechanistically, overexpression of TCF7L2 and EGR1 increased endogenous LCN2 expression via the ERK signaling pathway. Treatment with recombinant human LCN2 protein enhanced activation of the ERK pathway to facilitate endogenous LCN2 expression, as well as increase the expression level of TCF7L2 and EGR1. Treatment with the MEK inhibitor U0126 inhibited the activation by TCF7L2 or EGR1 overexpression. Moreover, overexpression of TCF7L2 or EGR1 accelerated the migration and invasion of ESCC cells. A synergistic effect was observed between TCF7L2 and EGR1 in amplifying the induction of LCN2 and enhancing migration and invasion. Taken together, our study indicates that TCF7L2 and EGR1 are the KTAPs of LCN2, within a positive “LCN2 → MEK/ERK → LCN2” path, to promote the migration and invasion of ESCC cells. Based on their clinicopathological significance, LCN2 and its two expression regulators TCF7L2 and ERG1 might be therapeutic targets for ESCC.
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TCF7L2 and EGR1 synergistic activation of transcription of LCN2 via an ERK1/2-dependent pathway in esophageal squamous cell carcinoma cells
Cellular signalling, 2018Co-Authors: Yan Zhao, Qiaoxi Xia, Yan Liu, Wen-jing Bai, Yubin Yao, Jiyu Ding, Ling Lin, Zhixiong Cai, Shao-hong WangAbstract:Abstract High level expression of lipocalin 2 (LCN2) usually indicates poor prognosis in esophageal squamous cell carcinoma (ESCC) and many other cancers. Our previous study showed LCN2 promotes migration and invasion of ESCC cells through a novel positive feedback loop. However, the key transcription activation protein (KTAP) in the loop had not yet been identified. In this study, we first predicted the most probable KTAPs by bioinformatic analysis. We then assessed the transcription regulatory regions in the human LCN2 gene by fusing deletions of its 5′-flanking region to a dual-luciferase reporter. We found that the region −720/−200 containing transcription factor 7-like 2 (TCF7L2) (−273/−209) and early growth response 1 (EGR1) (−710/−616) binding sites is crucial for LCN2 promoter activity. Chromatin immunoprecipitation (ChIP) experiments demonstrated that TCF7L2 and EGR1 bound directly to their binding sites within the LCN2 promoter as KTAPs. Mechanistically, overexpression of TCF7L2 and EGR1 increased endogenous LCN2 expression via the ERK signaling pathway. Treatment with recombinant human LCN2 protein enhanced activation of the ERK pathway to facilitate endogenous LCN2 expression, as well as increase the expression level of TCF7L2 and EGR1. Treatment with the MEK inhibitor U0126 inhibited the activation by TCF7L2 or EGR1 overexpression. Moreover, overexpression of TCF7L2 or EGR1 accelerated the migration and invasion of ESCC cells. A synergistic effect was observed between TCF7L2 and EGR1 in amplifying the induction of LCN2 and enhancing migration and invasion. Taken together, our study indicates that TCF7L2 and EGR1 are the KTAPs of LCN2, within a positive “LCN2 → MEK/ERK → LCN2” path, to promote the migration and invasion of ESCC cells. Based on their clinicopathological significance, LCN2 and its two expression regulators TCF7L2 and ERG1 might be therapeutic targets for ESCC.
Yan Wang - One of the best experts on this subject based on the ideXlab platform.
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Correction: Vitamin D promotes the cisplatin sensitivity of oral squamous cell carcinoma by inhibiting LCN2-modulated NF-κB pathway activation through RPS3.
Cell death & disease, 2020Co-Authors: Zixian Huang, Tingting Jin, Qianyu Zhang, Yin Zhang, Rui Chen, Yufeng Zhou, Yan WangAbstract:Chemoresistance is a major cause of cancer progression and the mortality of cancer patients. Developing a safe strategy for enhancing chemosensitivity is a challenge for biomedical science. Recent studies have suggested that vitamin D supplementation may decrease the risk of many cancers. However, the role of vitamin D in chemotherapy remains unknown. We found that vitamin D sensitised oral cancer cells to cisplatin and partially reversed cisplatin resistance. Using RNA-seq, we discovered that lipocalin 2 (LCN2) is an important mediator. Cisplatin enhanced the expression of LCN2 by decreasing methylation at the promoter, whereas vitamin D enhanced methylation and thereby inhibited the expression of LCN2. Overexpression of LCN2 increased cell survival and cisplatin resistance both in vitro and in vivo. High LCN2 expression was positively associated with differentiation, lymph node metastasis, and T staging and predicted a poor prognosis in oral squamous cell carcinoma (OSCC) patients. LCN2 was also associated with post-chemotherapy recurrence. Moreover, we found that LCN2 promoted the activation of NF-κB by binding to ribosomal protein S3 (RPS3) and enhanced the interaction between RPS3 and p65. Our study reveals that vitamin D can enhance cisplatin chemotherapy and suggests that vitamin D should be supplied during chemotherapy; however, more follow-up clinical studies are needed.
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Vitamin D promotes the cisplatin sensitivity of oral squamous cell carcinoma by inhibiting LCN2-modulated NF-κB pathway activation through RPS3
Cell Death & Disease, 2019Co-Authors: Zixian Huang, Tingting Jin, Kaishun Hu, Qianyu Zhang, Shihao Li, Haigang Li, Yin Zhang, Rui Chen, Yufeng Zhou, Yan WangAbstract:Chemoresistance is a major cause of cancer progression and the mortality of cancer patients. Developing a safe strategy for enhancing chemosensitivity is a challenge for biomedical science. Recent studies have suggested that vitamin D supplementation may decrease the risk of many cancers. However, the role of vitamin D in chemotherapy remains unknown. We found that vitamin D sensitised oral cancer cells to cisplatin and partially reversed cisplatin resistance. Using RNA-seq, we discovered that lipocalin 2 (LCN2) is an important mediator. Cisplatin enhanced the expression of LCN2 by decreasing methylation at the promoter, whereas vitamin D enhanced methylation and thereby inhibited the expression of LCN2. Overexpression of LCN2 increased cell survival and cisplatin resistance both in vitro and in vivo. High LCN2 expression was positively associated with differentiation, lymph node metastasis, and T staging and predicted a poor prognosis in oral squamous cell carcinoma (OSCC) patients. LCN2 was also associated with post-chemotherapy recurrence. Moreover, we found that LCN2 promoted the activation of NF-κB by binding to ribosomal protein S3 (RPS3) and enhanced the interaction between RPS3 and p65. Our study reveals that vitamin D can enhance cisplatin chemotherapy and suggests that vitamin D should be supplied during chemotherapy; however, more follow-up clinical studies are needed.
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inhibition of lipocalin 2 impairs breast tumorigenesis and metastasis
Cancer Research, 2009Co-Authors: Xiaohong Leng, Yan Wang, Tian Ding, Hui Lin, Barry W Feig, Wei Zhang, Lajos Pusztai, Fraser W Symmans, Ralph B ArlinghausAbstract:Lipocalin 2 (LCN2; also known as NGAL) is a secreted glycoprotein and its elevated expression has been observed in breast cancers. However, the importance of LCN2 in breast tumorigenesis is unclear. Here, we employed a spontaneous mammary tumor mouse model showing that MMTV-ErbB2(V664E) mice lacking mouse LCN2 had significantly delayed mammary tumor formation and metastasis with reduced matrix metalloproteinase-9 activity in the blood. LCN2 expression is upregulated by HER2/phosphoinositide 3-kinase/AKT/NF-kappaB pathway. Decreasing LCN2 expression significantly reduced the invasion and migration ability of HER2(+) breast cancer cells. Furthermore, injecting an anti-mouse LCN2 antibody into mice bearing established murine breast tumors resulted in significant blockage of lung metastasis. Our findings indicate that LCN2 is a critical factor in enhancing breast tumor formation and progression possibly in part by stabilizing matrix metalloproteinase-9. Our results suggest that inhibition of LCN2 function by an inhibitory monoclonal antibody has potential for breast cancer therapy, particularly by interfering with metastasis in aggressive types of breast cancer.
Natascha A Wolff - One of the best experts on this subject based on the ideXlab platform.
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tonicity inversely modulates lipocalin 2 LCN2 24p3 ngal receptor slc22a17 and LCN2 expression via wnt β catenin signaling in renal inner medullary collecting duct cells implications for cell fate and bacterial infection
Cell Communication and Signaling, 2018Co-Authors: R Betten, Bettina Scharner, Bayram Edemir, Christian Langelueddecke, Natascha A Wolff, S. Probst, Frank ThevenodAbstract:We have previously evidenced apical expression of the 24p3/NGAL/lipocalin-2 receptor (LCN2-R; SLC22A17) in inner medullary collecting duct (IMCD) cells, which are present in vivo in a hyperosmotic/-tonic environment that activates canonical Wnt/β-catenin signaling. The localization of LCN2-R in the inner medulla is intriguing considering local bacterial infections trigger toll-like receptor-4 (TLR-4)-mediated secretion of the bacteriostatic Fe3+-free (apo-)LCN2. To determine the effects of osmolarity/tonicity changes, Wnt/β-catenin and TLR-4 activation on LCN2-R and LCN2 expression and cell viability in rat primary IMCD and mouse (m)IMCD3 cells. Normosmolarity/-tonicity was 300 mosmol/l whereas hyperosmolarity/-tonicity was induced by adding 100 mmol/l NaCl + 100 mmol/l urea (600 mosmol/l, 1-7 days). LCN2-R and LCN2 expression were determined by qPCR, immunoblotting, flow cytometry and immunofluorescence microscopy. β-catenin was silenced by RNAi. Cell viability/death was determined with MTT and LDH release assays. TLR-4 was activated by bacterial lipopolysaccharides (LPS). Hyperosmotic/-tonic media upregulated LCN2-R by ~4-fold and decreased LCN2 expression/secretion, along with Wnt/β-catenin activation, in IMCD cells. These effects of hyperosmotic/-tonic media on LCN2-R/LCN2 expression were reverted by normosmolarity/-tonicity, β-catenin silencing and/or LPS. Exposure of cells with endogenous or stably overexpressing LCN2-R to apo-LCN2 or LPS decreased cell viability. LCN2-R upregulation and LCN2 downregulation via Wnt/β-catenin may promote adaptive osmotolerant survival of IMCD cells in response to hyperosmolarity/-tonicity whereas LCN2 upregulation and LCN2-R downregulation via TLR-4 and/or normosmolarity/-tonicity may protect IMCD cells against bacterial infections and prevent autocrine death induction by LCN2.
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Tonicity inversely modulates lipocalin-2 (LCN2/24p3/NGAL) receptor (SLC22A17) and LCN2 expression via Wnt/β-catenin signaling in renal inner medullary collecting duct cells: implications for cell fate and bacterial infection.
Cell communication and signaling : CCS, 2018Co-Authors: R Betten, Bettina Scharner, Bayram Edemir, Christian Langelueddecke, Natascha A Wolff, S. Probst, Wing-kee Lee, Frank ThevenodAbstract:We have previously evidenced apical expression of the 24p3/NGAL/lipocalin-2 receptor (LCN2-R; SLC22A17) in inner medullary collecting duct (IMCD) cells, which are present in vivo in a hyperosmotic/-tonic environment that activates canonical Wnt/β-catenin signaling. The localization of LCN2-R in the inner medulla is intriguing considering local bacterial infections trigger toll-like receptor-4 (TLR-4)-mediated secretion of the bacteriostatic Fe3+-free (apo-)LCN2. To determine the effects of osmolarity/tonicity changes, Wnt/β-catenin and TLR-4 activation on LCN2-R and LCN2 expression and cell viability in rat primary IMCD and mouse (m)IMCD3 cells. Normosmolarity/-tonicity was 300 mosmol/l whereas hyperosmolarity/-tonicity was induced by adding 100 mmol/l NaCl + 100 mmol/l urea (600 mosmol/l, 1-7 days). LCN2-R and LCN2 expression were determined by qPCR, immunoblotting, flow cytometry and immunofluorescence microscopy. β-catenin was silenced by RNAi. Cell viability/death was determined with MTT and LDH release assays. TLR-4 was activated by bacterial lipopolysaccharides (LPS). Hyperosmotic/-tonic media upregulated LCN2-R by ~4-fold and decreased LCN2 expression/secretion, along with Wnt/β-catenin activation, in IMCD cells. These effects of hyperosmotic/-tonic media on LCN2-R/LCN2 expression were reverted by normosmolarity/-tonicity, β-catenin silencing and/or LPS. Exposure of cells with endogenous or stably overexpressing LCN2-R to apo-LCN2 or LPS decreased cell viability. LCN2-R upregulation and LCN2 downregulation via Wnt/β-catenin may promote adaptive osmotolerant survival of IMCD cells in response to hyperosmolarity/-tonicity whereas LCN2 upregulation and LCN2-R downregulation via TLR-4 and/or normosmolarity/-tonicity may protect IMCD cells against bacterial infections and prevent autocrine death induction by LCN2.
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biochemical and structural characterization of the interaction between the siderocalin ngal LCN2 neutrophil gelatinase associated lipocalin lipocalin 2 and the n terminal domain of its endocytic receptor slc22a17
Journal of Biological Chemistry, 2016Co-Authors: Ana-isabel Cabedo Martinez, Natascha A Wolff, Wing-kee Lee, Katharina Weinhäupl, Barbara Storch, Robert Konrat, Wiktor Koźmiński, Kathrin Breuker, Szymon żerko, Frank ThevenodAbstract:The neutrophil gelatinase-associated lipocalin (NGAL, also known as LCN2) and its cellular receptor (LCN2-R, SLC22A17) are involved in many physiological and pathological processes such as cell differentiation, apoptosis, and inflammation. These pleiotropic functions mainly rely on NGAL's siderophore-mediated iron transport properties. However, the molecular determinants underlying the interaction between NGAL and its cellular receptor remain largely unknown. Here, using solution-state biomolecular NMR in conjunction with other biophysical methods, we show that the N-terminal domain of LCN2-R is a soluble extracellular domain that is intrinsically disordered and interacts with NGAL preferentially in its apo state to form a fuzzy complex. The relatively weak affinity (≈10 μm) between human LCN2-R-NTD and apoNGAL suggests that the N terminus on its own cannot account for the internalization of NGAL by LCN2-R. However, human LCN2-R-NTD could be involved in the fine-tuning of the interaction between NGAL and its cellular receptor or in a biochemical mechanism allowing the receptor to discriminate between apo- and holo-NGAL.
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Biochemical and Structural Characterization of the Interaction between the Siderocalin NGAL/LCN2 (Neutrophil Gelatinase-associated Lipocalin/Lipocalin 2) and the N-terminal Domain of Its Endocytic Receptor SLC22A17.
The Journal of biological chemistry, 2015Co-Authors: Ana-isabel Cabedo Martinez, Natascha A Wolff, Wing-kee Lee, Katharina Weinhäupl, Barbara Storch, Szymon Żerko, Robert Konrat, Wiktor Koźmiński, Kathrin Breuker, Frank ThevenodAbstract:The neutrophil gelatinase-associated lipocalin (NGAL, also known as LCN2) and its cellular receptor (LCN2-R, SLC22A17) are involved in many physiological and pathological processes such as cell differentiation, apoptosis, and inflammation. These pleiotropic functions mainly rely on NGAL's siderophore-mediated iron transport properties. However, the molecular determinants underlying the interaction between NGAL and its cellular receptor remain largely unknown. Here, using solution-state biomolecular NMR in conjunction with other biophysical methods, we show that the N-terminal domain of LCN2-R is a soluble extracellular domain that is intrinsically disordered and interacts with NGAL preferentially in its apo state to form a fuzzy complex. The relatively weak affinity (≈10 μm) between human LCN2-R-NTD and apoNGAL suggests that the N terminus on its own cannot account for the internalization of NGAL by LCN2-R. However, human LCN2-R-NTD could be involved in the fine-tuning of the interaction between NGAL and its cellular receptor or in a biochemical mechanism allowing the receptor to discriminate between apo- and holo-NGAL.
Yan Zhao - One of the best experts on this subject based on the ideXlab platform.
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LCN2-interacting proteins and their expression patterns in brain tumors
Brain research, 2019Co-Authors: Qiaoxi Xia, Yan Zhao, Ling Lin, Zhixiong Cai, Shao-hong WangAbstract:Lipocalin 2 (LCN2) is a member of the lipocalin family. Elevated expression of LCN2 has been observed in many human tumors, suggesting it might be a potential biomarker and/or therapeutic target in malignancies. In this study, we aimed to explore LCN2 interacting proteins through bioinformatics, as well as their biological functions. Protein-protein interaction networks (PPIN) were constructed using LCN2 and its interacting proteins as the core node. These PPINs were scale free biological networks in which LCN2 and its interacting proteins could connect or cross-talk with at least one partner protein. Both functional and KEGG pathway enrichment analyses identified the known and potential biological functions of the PPIN, such as cell migration and cancer-related pathways. Expression levels of the PPIN proteins, as well as their expression correlations, in five types of brain tumor, were analyzed and integrated into the PPIN to illustrate a dynamic change. A significant correlation was found between the survival time of glioblastoma patients and the expression level of 10 genes (LCN2, MMP9, MMP2, PDE4DIP, L2HGDH, HNRNPA1, DDX31, LOXL2, FAM60A and RNF25). Taken together, our results suggest that LCN2 and its interacting proteins are mostly differentially expressed and have a distinguishing co-expression pattern. They might promote proliferation and migration via cell migration signaling and cancer-related pathways. LCN2 and its interacting proteins might be potential biomarkers in glioblastoma.
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tcf7l2 and egr1 synergistic activation of transcription of LCN2 via an erk1 2 dependent pathway in esophageal squamous cell carcinoma cells
Cellular Signalling, 2019Co-Authors: Yan Zhao, Qiaoxi Xia, Yan Liu, Wen-jing Bai, Yubin Yao, Jiyu Ding, Ling Lin, Zhixiong Cai, Shao-hong WangAbstract:Abstract High level expression of lipocalin 2 (LCN2) usually indicates poor prognosis in esophageal squamous cell carcinoma (ESCC) and many other cancers. Our previous study showed LCN2 promotes migration and invasion of ESCC cells through a novel positive feedback loop. However, the key transcription activation protein (KTAP) in the loop had not yet been identified. In this study, we first predicted the most probable KTAPs by bioinformatic analysis. We then assessed the transcription regulatory regions in the human LCN2 gene by fusing deletions of its 5′-flanking region to a dual-luciferase reporter. We found that the region −720/−200 containing transcription factor 7-like 2 (TCF7L2) (−273/−209) and early growth response 1 (EGR1) (−710/−616) binding sites is crucial for LCN2 promoter activity. Chromatin immunoprecipitation (ChIP) experiments demonstrated that TCF7L2 and EGR1 bound directly to their binding sites within the LCN2 promoter as KTAPs. Mechanistically, overexpression of TCF7L2 and EGR1 increased endogenous LCN2 expression via the ERK signaling pathway. Treatment with recombinant human LCN2 protein enhanced activation of the ERK pathway to facilitate endogenous LCN2 expression, as well as increase the expression level of TCF7L2 and EGR1. Treatment with the MEK inhibitor U0126 inhibited the activation by TCF7L2 or EGR1 overexpression. Moreover, overexpression of TCF7L2 or EGR1 accelerated the migration and invasion of ESCC cells. A synergistic effect was observed between TCF7L2 and EGR1 in amplifying the induction of LCN2 and enhancing migration and invasion. Taken together, our study indicates that TCF7L2 and EGR1 are the KTAPs of LCN2, within a positive “LCN2 → MEK/ERK → LCN2” path, to promote the migration and invasion of ESCC cells. Based on their clinicopathological significance, LCN2 and its two expression regulators TCF7L2 and ERG1 might be therapeutic targets for ESCC.
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TCF7L2 and EGR1 synergistic activation of transcription of LCN2 via an ERK1/2-dependent pathway in esophageal squamous cell carcinoma cells
Cellular signalling, 2018Co-Authors: Yan Zhao, Qiaoxi Xia, Yan Liu, Wen-jing Bai, Yubin Yao, Jiyu Ding, Ling Lin, Zhixiong Cai, Shao-hong WangAbstract:Abstract High level expression of lipocalin 2 (LCN2) usually indicates poor prognosis in esophageal squamous cell carcinoma (ESCC) and many other cancers. Our previous study showed LCN2 promotes migration and invasion of ESCC cells through a novel positive feedback loop. However, the key transcription activation protein (KTAP) in the loop had not yet been identified. In this study, we first predicted the most probable KTAPs by bioinformatic analysis. We then assessed the transcription regulatory regions in the human LCN2 gene by fusing deletions of its 5′-flanking region to a dual-luciferase reporter. We found that the region −720/−200 containing transcription factor 7-like 2 (TCF7L2) (−273/−209) and early growth response 1 (EGR1) (−710/−616) binding sites is crucial for LCN2 promoter activity. Chromatin immunoprecipitation (ChIP) experiments demonstrated that TCF7L2 and EGR1 bound directly to their binding sites within the LCN2 promoter as KTAPs. Mechanistically, overexpression of TCF7L2 and EGR1 increased endogenous LCN2 expression via the ERK signaling pathway. Treatment with recombinant human LCN2 protein enhanced activation of the ERK pathway to facilitate endogenous LCN2 expression, as well as increase the expression level of TCF7L2 and EGR1. Treatment with the MEK inhibitor U0126 inhibited the activation by TCF7L2 or EGR1 overexpression. Moreover, overexpression of TCF7L2 or EGR1 accelerated the migration and invasion of ESCC cells. A synergistic effect was observed between TCF7L2 and EGR1 in amplifying the induction of LCN2 and enhancing migration and invasion. Taken together, our study indicates that TCF7L2 and EGR1 are the KTAPs of LCN2, within a positive “LCN2 → MEK/ERK → LCN2” path, to promote the migration and invasion of ESCC cells. Based on their clinicopathological significance, LCN2 and its two expression regulators TCF7L2 and ERG1 might be therapeutic targets for ESCC.