scholarly journals Secreted CXCL12 (SDF-1) forms dimers under physiological conditions

2012 ◽  
Vol 442 (2) ◽  
pp. 433-442 ◽  
Author(s):  
Paramita Ray ◽  
Sarah A. Lewin ◽  
Laura Anne Mihalko ◽  
Sasha-Cai Lesher-Perez ◽  
Shuichi Takayama ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Extracellular Space ◽  
Mammalian Cells ◽  
Cell Signalling ◽  
Xenograft Model ◽  
Physiological Conditions ◽  
Cxc Chemokine ◽  
Chemokine Ligand ◽  
Chemokine Cxcl12 ◽  
And Function

Chemokine CXCL12 (CXC chemokine ligand 12) signalling through CXCR (CXC chemokine receptor) 4 and CXCR7 has essential functions in development and underlies diseases including cancer, atherosclerosis and autoimmunity. Chemokines may form homodimers that regulate receptor binding and signalling, but previous studies with synthetic CXCL12 have produced conflicting evidence for homodimerization. We used bioluminescence imaging with GL (Gaussia luciferase) fusions to investigate dimerization of CXCL12 secreted from mammalian cells. Using column chromatography and GL complementation, we established that CXCL12 was secreted from mammalian cells as both monomers and dimers. Secreted CXCL12 also formed homodimers in the extracellular space. Monomeric CXCL12 preferentially activated CXCR4 signalling through Gαi and Akt, whereas dimeric CXCL12 more effectively promoted recruitment of β-arrestin 2 to CXCR4 and chemotaxis of CXCR4-expressing breast cancer cells. We also showed that CXCR7 preferentially sequestered monomeric CXCL12 from the extracellular space and had minimal effects on dimeric CXCL12 in cell-based assays and an orthotopic tumour xenograft model of human breast cancer. These studies establish that CXCL12 secreted from mammalian cells forms homodimers under physiological conditions. Since monomeric and dimeric CXCL12 have distinct effects on cell signalling and function, our results have important implications for ongoing efforts to target CXCL12 pathways for therapy.

scholarly journals Role of CXC Chemokine Ligand 13, CC Chemokine Ligand (CCL) 19, and CCL21 in the Organization and Function of Nasal-Associated Lymphoid Tissue

2005 ◽  
Vol 175 (8) ◽  
pp. 4904-4913 ◽  
Author(s):  
Javier Rangel-Moreno ◽  
Juan Moyron-Quiroz ◽  
Kim Kusser ◽  
Louise Hartson ◽  
Hideki Nakano ◽  
...  
Keyword(s):  
Lymphoid Tissue ◽  
Cc Chemokine ◽  
Cxc Chemokine ◽  
Chemokine Ligand ◽  
And Function

scholarly journals mTORC2 Drives ZFX-mediated Ganglioside Biosynthesis to Promote Breast Cancer Progression.

2022 ◽  
Author(s):  
Kajal Rajput ◽  
Mohammad Nafees Ansari ◽  
Somesh Kumar Jha ◽  
Pankaj Sharma ◽  
Sudeshna Datta ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Progression ◽  
Mammalian Cells ◽  
Zinc Finger Protein ◽  
Cell Signalling ◽  
Dna Methyltransferases ◽  
Breast Cancer Progression ◽  
Regulatory Subunit ◽  
Luminal Breast Cancer ◽  
Invasion And Migration

Sphingolipid and ganglioside metabolic pathways are crucial components of cell signalling, having established roles in tumor cell proliferation, invasion, and migration. However, regulatory mechanisms controlling sphingolipid and ganglioside synthesis in mammalian cells is less known. Here, we show that RICTOR, the regulatory subunit of mTORC2, regulates the synthesis of sphingolipids and gangliosides in Luminal breast cancer-specific MCF-7 cells through transcriptional and epigenetic mechanisms. RICTOR regulates glucosylceramide levels by modulating the expression of UDP-Glucose Ceramide Glucosyl transferase (UGCG). We identify Zinc Finger protein X-linked (ZFX) as a RICTOR-responsive transcription factor whose recruitment to the UGCG promoter is regulated by DNA methyltransferases and histone demethylase (KDM5A) that are known AKT substrates. We further demonstrate that RICTOR regulates the synthesis of GD3 gangliosides through ZFX and UGCG, and triggers the activation of the EGFR signalling pathway, thereby promoting tumor growth. In line with our findings in cell culture and mice models, we observe an elevated expression of RICTOR, ZFX, and UGCG in Indian Luminal breast cancer patient samples, and in TCGA and METABRIC datasets. Together, we establish a key regulatory circuit, RICTOR-AKT-ZFX-UGCG-Ganglioside-EGFR-AKT, and elucidate its contribution to breast cancer progression.

scholarly journals System-L amino acid transporters play a key role in pancreatic β-cell signalling and function

2016 ◽  
Vol 56 (3) ◽  
pp. 175-187 ◽  
Author(s):  
Qi Cheng ◽  
Violeta D Beltran ◽  
Stanley M H Chan ◽  
Jeremy R Brown ◽  
Alan Bevington ◽  
...  
Keyword(s):  
Amino Acids ◽  
Insulin Secretion ◽  
Amino Acid ◽  
Mammalian Cells ◽  
Critical Role ◽  
Cell Signalling ◽  
Amino Acid Transporters ◽  
Β Cell ◽  
System L ◽  
And Function

Abstract The branched-chain amino acids (BCAA) leucine, isoleucine and valine, are essential amino acids that play a critical role in cellular signalling and metabolism. They acutely stimulate insulin secretion and activate the regulatory serine/threonine kinase mammalian target of rapamycin complex 1 (mTORC1), a kinase that promotes increased β-cell mass and function. The effects of BCAA on cellular function are dependent on their active transport into the mammalian cells via amino acid transporters and thus the expression and activity of these transporters likely influence β-cell signalling and function. In this report, we show that the System-L transporters are required for BCAA uptake into clonal β-cell lines and pancreatic islets, and that these are essential for signalling to mTORC1. Further investigation revealed that the System-L amino acid transporter 1 (LAT1) is abundantly expressed in the islets, and that knockdown of LAT1 using siRNA inhibits mTORC1 signalling, leucine-stimulated insulin secretion and islet cell proliferation. In summary, we show that the LAT1 is required for regulating β-cell signalling and function in islets and thus may be a novel pharmacological/nutritional target for the treatment and prevention of type 2 diabetes.

scholarly journals CXC Chemokine CXCL12 and Its Receptor CXCR4 in Tree Shrews (Tupaia belangeri): Structure, Expression and Function

PLoS ONE ◽  
2014 ◽  
Vol 9 (5) ◽  
pp. e98231 ◽  
Author(s):  
Guiyuan Chen ◽  
Wei Wang ◽  
Shengke Meng ◽  
Lichao Zhang ◽  
Wenxue Wang ◽  
...  
Keyword(s):  
Tree Shrews ◽  
Tupaia Belangeri ◽  
Cxc Chemokine ◽  
Chemokine Cxcl12 ◽  
And Function

scholarly journals Traditional Chinese Medicine Extract from Huaier Increases the Expression of Duffy Antigen Receptor for Chemokines and Reduces the Expression of Its Ligands

2018 ◽  
Vol 2018 ◽  
pp. 1-8
Author(s):  
Ying Chen ◽  
Qianjun Chen ◽  
Fengfeng Xie ◽  
Hui Peng ◽  
Yanlan Wu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Chinese Medicine ◽  
Traditional Chinese Medicine ◽  
Aqueous Extract ◽  
Antigen Receptor ◽  
Matrix Metalloproteinase 2 ◽  
Enzyme Linked Immunosorbent Assay ◽  
Duffy Antigen ◽  
Cxc Chemokine ◽  
Chemokine Ligand

Aims. The aim of the present study is to investigate whether the aqueous extract from Huaier, a traditional Chinese medicine (TCM), can affect the expression of Duffy antigen receptor for chemokines (DARC) and its ligands. Moreover, we compare the status of DARC in primary and metastatic breast cancer tissues from the same patient. Methods. Immunohistochemistry was used to detect the expression of DARC in primary and metastatic focuses in 30 patients with breast cancer. The effect of Huaier aqueous extract on the expression of DARC and its ligands was investigated by quantitative real-time polymerase chain reaction, Western blotting, and enzyme-linked immunosorbent assay. Results. The expression score of DARC in primary focuses was significantly higher than that in metastatic focuses, while changes of ER, PR, and HER2 receptors were not significantly different between primary and metastatic focuses. Huaier aqueous extract promoted the expression of DARC and reduced the secretion of CC chemokine ligand 2 (CCL-2), CXC chemokine ligand 8 (CXCL-8, IL-8), matrix metalloproteinase 2 (MMP-2), and CXC chemokine ligand 1 (CXCL-1). Conclusion. The present study demonstrates that difference in expression level of DARC between primary and metastatic focuses of breast cancer was significant, while differences in expression of ER, PR, and HER2 between primary and metastatic focuses were not significant. DARC may play a negative role in the metastasis of breast cancer. Traditional Chinese medicine extract from Huaier can increase DARC expression and reduce the expression of its ligands such as CCL-2, IL-8, MMP-2, and CXCL-1.

Scanning electron microscopic study of collagen fibrillogenesis and extracellular compartmentalization in the chick embryo tendon

1986 ◽  
Vol 44 ◽  
pp. 208-209
Author(s):  
Grace C.H. Yang
Keyword(s):  
Chick Embryo ◽  
Extracellular Space ◽  
Fibroblast Cell ◽  
Collagen Fibrils ◽  
Electron Microscopic ◽  
Voltage Electron ◽  
Scanning Electron Microscopic Study ◽  
Microscopic Studies ◽  
And Function

The size and organization of collagen fibrils in the extracellular matrix is an important determinant of tissue structure and function. The synthesis and deposition of collagen involves multiple steps which begin within the cell and continue in the extracellular space. High-voltage electron microscopic studies of the chick embryo cornea and tendon suggested that the extracellular space is compartmentalized by the fibroblasts for the regulation of collagen fibril, bundle, and tissue specific macroaggregate formation. The purpose of this study is to gather direct evidence regarding the association of the fibroblast cell surface with newly formed collagen fibrils, and to define the role of the fibroblast in the control and the precise positioning of collagen fibrils, bundles, and macroaggregates during chick tendon development.

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