12 results on '"Feniger-Barish R"'
Search Results
2. Melanoma cells exhibit strong intracellular TASK-3-specific immunopositivity in both tissue sections and cell culture
- Author
-
Pocsai, K., Kosztka, L., Bakondi, G., Gönczi, M., Fodor, J., Dienes, B., Szentesi, P., Kovács, I., Feniger-Barish, R., Kopf, E., Zharhary, D., Szűcs, G., Csernoch, L., and Rusznák, Z.
- Published
- 2006
- Full Text
- View/download PDF
3. Melanoma cells exhibit strong intracellular TASK-3-specific immunopositivity in both tissue sections and cell culture
- Author
-
Ilona Kovács, Lívia Kosztka, Zoltán Rusznák, Géza Szucs, Feniger-Barish R, Beatrix Dienes, László Csernoch, Kopf E, Péter Szentesi, Krisztina Pocsai, Mónika Gönczi, Gábor Bakondi, János Fodor, and Zharhary D
- Subjects
medicine.drug_class ,Recombinant Fusion Proteins ,Immunocytochemistry ,Green Fluorescent Proteins ,Biology ,Monoclonal antibody ,behavioral disciplines and activities ,Epitope ,Cellular and Molecular Neuroscience ,Immunocompromised Host ,Mice ,Potassium Channels, Tandem Pore Domain ,Western blot ,Cell Line, Tumor ,medicine ,Animals ,Humans ,Elméleti orvostudományok ,Molecular Biology ,Melanoma ,Pharmacology ,medicine.diagnostic_test ,Cell Biology ,Transfection ,Orvostudományok ,medicine.disease ,Molecular biology ,Immunohistochemistry ,Rats ,Cell culture ,Molecular Medicine ,Melanocytes ,psychological phenomena and processes - Abstract
Amplification of the kcnk9 gene and overexpression of the encoded channel protein (TASK-3) seems to be involved in carcinogenesis. In the present work, TASK-3 expression of melanoma cells has been studied. For the investigation of TASK-3-specific immunolabelling, a monoclonal antibody has been developed and applied along with two, commercially available polyclonal antibodies targeting different epitopes of the channel protein. Both primary and metastatic melanoma cells proved to be TASK-3 positive, showing prominent intracellular TASK-3-specific labelling; mostly concentrating around or in the proximity of the nuclei. The immunoreaction was associated with the nuclear envelope, and with the processes of the cells and it was also present in the cell surface membrane. Specificity of the immunolabelling was confirmed by Western blot and transfection experiments. As TASK-3 immunopositivity of benign melanocytes could also be demonstrated, the presence or absence of TASK-3 channels cannot differentiate between malignant and non-malignant melanocytic tumours.
- Published
- 2006
4. Cancer cells suppress p53 in adjacent fibroblasts
- Author
-
Bar, J, primary, Feniger-Barish, R, additional, Lukashchuk, N, additional, Shaham, H, additional, Moskovits, N, additional, Goldfinger, N, additional, Simansky, D, additional, Perlman, M, additional, Papa, M, additional, Yosepovich, A, additional, Rechavi, G, additional, Rotter, V, additional, and Oren, M, additional
- Published
- 2008
- Full Text
- View/download PDF
5. Stromal-MDM2 Promotes Lung Cancer Cell Invasion through Tumor-Host Feedback Signaling.
- Author
-
Kamer I, Daniel-Meshulam I, Zadok O, Bab-Dinitz E, Perry G, Feniger-Barish R, Perelman M, Barshack I, Ben-Nun A, Onn A, and Bar J
- Subjects
- Animals, Apoptosis, Biomarkers, Tumor genetics, Cell Proliferation, Culture Media, Conditioned metabolism, Female, Fibroblasts metabolism, Gene Expression Regulation, Neoplastic, Humans, Lung Neoplasms genetics, Lung Neoplasms metabolism, Mice, Mice, Nude, Neoplasm Invasiveness, Proto-Oncogene Proteins c-mdm2 genetics, Tumor Cells, Cultured, Xenograft Model Antitumor Assays, Biomarkers, Tumor metabolism, Feedback, Physiological, Fibroblasts pathology, Lung Neoplasms pathology, Proto-Oncogene Proteins c-mdm2 metabolism, Stromal Cells metabolism
- Abstract
Tumor-host interactions play a major role in malignancies' initiation and progression. We have reported in the past that tumor cells attenuate genotoxic stress-induced p53 activation in neighboring stromal cells. Herein, we aim to further elucidate cancer cells' impact on signaling within lung cancer stroma. Primary cancer-associated fibroblasts were grown from resected human lung tumors. Lung cancer lines as well as fresh cultures of resected human lung cancers were used to produce conditioned medium (CM) or cocultured with stromal cells. Invasiveness of cancer cells was evaluated by transwell assays, and in vivo tumor growth was tested in Athymic nude mice. We found CM of a large variety of cancer cell lines as well as ex vivo -cultured lung cancers to rapidly induce protein levels of stromal-MDM2. CM of nontransformed cells had no such effect. Mdm2 induction occurred through enhanced translation, was mTORC1-dependent, and correlated with activation of AKT and p70 S6 Kinase. AKT or MDM2 knockdown in fibroblasts reduced the invasion of neighboring cancer cells, independently of stromal-p53. MDM2 overexpression in fibroblasts enhanced cancer cells' invasion and growth of inoculated tumors in mice. Our results indicate that stromal-MDM2 participates in a p53-independent cancer-host feedback mechanism. Soluble cancer-originated signals induce enhanced translation of stromal-MDM2 through AKT/mTORC1 signaling, which in turn enhances the neighboring cancer cells' invasion ability. The role of these tumor-host interactions needs to be further explored. IMPLICATIONS: We uncovered a novel tumor-stroma signaling loop, which is a potentially new therapeutic target in lung cancer and possibly in additional types of cancer., (©2020 American Association for Cancer Research.)
- Published
- 2020
- Full Text
- View/download PDF
6. Regulation of the inflammatory profile of stromal cells in human breast cancer: prominent roles for TNF-α and the NF-κB pathway.
- Author
-
Katanov C, Lerrer S, Liubomirski Y, Leider-Trejo L, Meshel T, Bar J, Feniger-Barish R, Kamer I, Soria-Artzi G, Kahani H, Banerjee D, and Ben-Baruch A
- Subjects
- Blotting, Western, Bone Marrow Cells cytology, Breast Neoplasms metabolism, Cell Line, Tumor, Cell Movement drug effects, Chemokine CCL2 analysis, Chemokine CCL5 analysis, Culture Media, Conditioned pharmacology, Female, Fibroblasts cytology, Humans, Interleukin-1beta pharmacology, Interleukin-8 analysis, JNK Mitogen-Activated Protein Kinases antagonists & inhibitors, JNK Mitogen-Activated Protein Kinases genetics, JNK Mitogen-Activated Protein Kinases metabolism, MCF-7 Cells, Mesenchymal Stem Cells cytology, Mesenchymal Stem Cells metabolism, RNA Interference, Signal Transduction, Transcription Factor RelA antagonists & inhibitors, Transcription Factor RelA genetics, Transcription Factor RelA metabolism, Tumor Necrosis Factor-alpha genetics, Tumor Necrosis Factor-alpha metabolism, Up-Regulation drug effects, Breast Neoplasms pathology, Fibroblasts metabolism, Mesenchymal Stem Cells drug effects, NF-kappa B metabolism, Tumor Necrosis Factor-alpha pharmacology
- Abstract
Introduction: Breast cancer progression is promoted by stromal cells that populate the tumors, including cancer-associated fibroblasts (CAFs) and mesenchymal stem/stromal cells (MSCs). The activities of CAFs and MSCs in breast cancer are integrated within an intimate inflammatory tumor microenvironment (TME) that includes high levels of tumor necrosis factor α (TNF-α) and interleukin 1β (IL-1β). Here, we identified the impact of TNF-α and IL-1β on the inflammatory phenotype of CAFs and MSCs by determining the expression of inflammatory chemokines that are well-characterized as pro-tumorigenic in breast cancer: CCL2 (MCP-1), CXCL8 (IL-8) and CCL5 (RANTES)., Methods: Chemokine expression was determined in breast cancer patient-derived CAFs by ELISA and in patient biopsies by immunohistochemistry. Chemokine levels were determined by ELISA in (1) human bone marrow-derived MSCs stimulated by tumor conditioned media (Tumor CM) of breast tumor cells (MDA-MB-231 and MCF-7) at the end of MSC-to-CAF-conversion process; (2) Tumor CM-derived CAFs, patient CAFs and MSCs stimulated by TNF-α (and IL-1β). The roles of AP-1 and NF-κB in chemokine secretion were analyzed by Western blotting and by siRNAs to c-Jun and p65, respectively. Migration of monocytic cells was determined in modified Boyden chambers., Results: TNF-α (and IL-1β) induced the release of CCL2, CXCL8 and CCL5 by MSCs and CAFs generated by prolonged stimulation of MSCs with Tumor CM of MDA-MB-231 and MCF-7 cells. Patient-derived CAFs expressed CCL2 and CXCL8, and secreted CCL5 following TNF-α (and IL-1β) stimulation. CCL2 was expressed in CAFs residing in proximity to breast tumor cells in biopsies of patients diagnosed with invasive ductal carcinoma. CCL2 release by TNF-α-stimulated MSCs was mediated by TNF-RI and TNF-RII, through the NF-κB but not via the AP-1 pathway. Exposure of MSCs to TNF-α led to potent CCL2-induced migration of monocytic cells, a process that may yield pro-cancerous myeloid infiltrates in breast tumors., Conclusions: Our novel results emphasize the important roles of inflammation-stroma interactions in breast cancer, and suggest that NF-κB may be a potential target for inhibition in tumor-adjacent stromal cells, enabling improved tumor control in inflammation-driven malignancies.
- Published
- 2015
- Full Text
- View/download PDF
7. Role of CXCR3 carboxyl terminus and third intracellular loop in receptor-mediated migration, adhesion and internalization in response to CXCL11.
- Author
-
Dagan-Berger M, Feniger-Barish R, Avniel S, Wald H, Galun E, Grabovsky V, Alon R, Nagler A, Ben-Baruch A, and Peled A
- Subjects
- Amino Acid Sequence, Amino Acid Substitution, Biological Transport, Calcium metabolism, Calcium Signaling, Cell Line, Chemokine CXCL11, DNA Primers, Fibronectins physiology, Gene Transfer Techniques, Humans, Kidney, Molecular Sequence Data, Mutagenesis, Site-Directed, Plasmids, Receptors, CXCR3, Receptors, Chemokine chemistry, Receptors, Chemokine genetics, Recombinant Proteins metabolism, Transfection, Vascular Cell Adhesion Molecule-1 physiology, Cell Adhesion physiology, Cell Movement physiology, Chemokines, CXC physiology, Receptors, Chemokine physiology
- Abstract
The chemokine receptor CXCR3 is predominantly expressed on activated T and natural killer (NK) cells. CXCR3 and its ligands, CXCL11, CXCL10, and CXCL9, play a major role in T-helper 1 (Th1)-dependent inflammatory responses. CXCL11 is the most dominant physiological inducer of adhesion, migration, and internalization of CXCR3. To study the role of CXCR3 carboxyl-terminus and the third intracellular (3i) loop in chemokine-mediated migration, adhesion, and CXCR3 internalization, we generated CXCR3 receptors mutated in their distal (Ser-Thr domain) or proximal (trileucine domain) membrane carboxyl terminus, and/or the third intracellular loop. We found that migration of CXCR3-expressing HEK 293 cells toward CXCL11 was pertussis toxin-dependent and required the membrane proximal carboxyl terminus of CXCR3. Internalization induced by CXCL11 and protein kinase C (PKC) activation was also regulated by the membrane proximal carboxyl terminus; however, only CXCL11-induced internalization required the LLL motif of this region. Internalization and Ca(2+) flux induced by CXCL11 were independent of the 3i loop S245, whereas migration at high CXCL11 concentrations, integrin-dependent adhesion, and actin polymerization were S245 dependent. Our findings indicate that CXCL11-dependent CXCR3 internalization and cell migration are regulated by the CXCR3 membrane proximal carboxyl terminus, whereas adhesion is regulated by the 3i loop S245. Thus, distinct conformational changes induced by a given CXCR3 ligand trigger different downstream effectors of adhesion, motility, and CXCR3 desensitization.
- Published
- 2006
- Full Text
- View/download PDF
8. IL-8-induced migratory responses through CXCR1 and CXCR2: association with phosphorylation and cellular redistribution of focal adhesion kinase.
- Author
-
Feniger-Barish R, Yron I, Meshel T, Matityahu E, and Ben-Baruch A
- Subjects
- Animals, Cell Line, Cell Migration Inhibition, Focal Adhesion Kinase 1, Focal Adhesion Protein-Tyrosine Kinases, Focal Adhesions enzymology, Focal Adhesions physiology, Humans, Inflammation enzymology, Inflammation pathology, Neutrophil Infiltration, Phosphorylation, Protein-Tyrosine Kinases biosynthesis, Protein-Tyrosine Kinases genetics, Protein-Tyrosine Kinases physiology, Rats, Transfection, Tumor Cells, Cultured, Tyrosine metabolism, Chemotaxis, Leukocyte physiology, Interleukin-8 physiology, Protein-Tyrosine Kinases metabolism, Receptors, Interleukin-8A physiology, Receptors, Interleukin-8B physiology
- Abstract
CXCR1 and CXCR2 mediate migratory activities in response to IL-8 and other ELR+-CXC chemokines (e.g., GCP-2 and NAP-2). In vitro, activation of migration is induced by low IL-8 concentrations (10-50 ng/mL), whereas migratory shut-off is induced by high IL-8 concentrations (1000 ng/mL). The stimulation of CXCR1 and CXCR2 by IL-8 concentrations that result in migratory activation induced focal adhesion kinase (FAK) phosphorylation in a G(alpha)i-dependent manner. The expression of FRNK, a dominant negative mutant of FAK, perturbed migratory responses to the activating dose of 50 ng/mL IL-8. The migration-activating concentrations of 50 ng/mL GCP-2 and NAP-2 induced less potent migratory responses and FAK phosphorylation in CXCR2-expressing cells as compared with IL-8. These results indicate that FAK is phosphorylated, and required, for the chemotactic response under conditions of migratory activation by ELR+-CXC chemokines. In addition, FAK phosphorylation was determined following exposure to migration-attenuating concentrations of IL-8. In CXCR1-RBL cells this treatment resulted in FAK phosphorylation, in similar levels to those induced by activating concentrations of IL-8. In contrast, in CXCR2-RBL cells the migration-attenuating concentrations of IL-8 induced promoted levels of FAK phosphorylation and different patterns of FAK phosphorylation on its six potential tyrosine phosphorylation sites, as compared to activating concentrations of the chemokine. Exposure to IL-8 resulted not only in FAK phosphorylation but also in its cellular redistribution, indicated by the formation of defined contact regions with the substratum, enriched in phosphorylated FAK and vinculin. Overall, FAK phosphorylation was associated with, and found to be differently regulated upon, ELR+-CXC chemokine-induced migration.
- Published
- 2003
- Full Text
- View/download PDF
9. Intracellular trafficking of human CXCR1 and CXCR2: regulation by receptor domains and actin-related kinases.
- Author
-
Matityahu E, Feniger-Barish R, Meshel T, Zaslaver A, and Ben-Baruch A
- Subjects
- Amino Acid Motifs, Amino Acid Sequence, Androstadienes pharmacology, Binding Sites, Cell Line, Humans, Molecular Sequence Data, Phosphatidylinositol 3-Kinases metabolism, Phosphoinositide-3 Kinase Inhibitors, Phosphorylation, Protein Serine-Threonine Kinases metabolism, Protein Structure, Tertiary, Receptors, Interleukin-8A genetics, Receptors, Interleukin-8B genetics, Recombinant Fusion Proteins chemistry, Recombinant Fusion Proteins genetics, Recombinant Fusion Proteins metabolism, Wortmannin, Receptors, Interleukin-8A chemistry, Receptors, Interleukin-8A metabolism, Receptors, Interleukin-8B chemistry, Receptors, Interleukin-8B metabolism
- Abstract
In this study we investigated the regulation of CXCR1 and CXCR2 intracellular trafficking. First, we produced a chimeric CXCR2 receptor that contained the internalization motifs of both CXCR2 and CXCR1 (CXCR2: LLKIL sequence; CXCR1: C-terminal phosphorylation sites). Elevated levels of internalization were induced by different ELR-expressing CXC chemokines on the chimeric receptor, as compared to wild-type CXCR2. Analysis of inter-relationships between CXCR1 and CXCR2 during internalization indicated that the exposure of cells that expressed both CXCR1 and CXCR2 to CXCL8 or CXCL6 resulted in decreased levels of CXCR1 internalization as compared to those in cells that expressed only CXCR1. To characterize the role of actin-related components in CXCR1 and CXCR2 trafficking, wortmannin, a potent inhibitor of phosphatidylinositol kinases, was used. The presence of wortmannin during receptor recycling inhibited CXCR1 and CXCR2 re-expression following CXCL8-induced internalization, and resulted in a marked disruption of the proper organization of actin filaments. The kinase-dependent recycling process required CXCR2 C-terminal phosphorylation sites. Our results suggest that actin-related kinases are required for the proper functionality of actin filaments, which are the instrumental factors needed for receptor recycling. In all, CXCR1 and CXCR2 internalization and recycling are tightly regulated by receptor domains and by actin-related kinases.
- Published
- 2002
- Full Text
- View/download PDF
10. Actin filaments are involved in the regulation of trafficking of two closely related chemokine receptors, CXCR1 and CXCR2.
- Author
-
Zaslaver A, Feniger-Barish R, and Ben-Baruch A
- Subjects
- Actins antagonists & inhibitors, Amino Acid Sequence, Biological Transport drug effects, Biological Transport genetics, Biological Transport immunology, Cell Line, Cell Membrane drug effects, Cell Membrane immunology, Cell Membrane metabolism, Cell Migration Inhibition, Chemotaxis drug effects, Chemotaxis genetics, Chemotaxis immunology, Cytochalasin D pharmacology, Down-Regulation drug effects, Down-Regulation genetics, Down-Regulation immunology, Humans, Interleukin-8 pharmacology, Molecular Sequence Data, Mutagenesis, Site-Directed, Neutrophils drug effects, Neutrophils immunology, Neutrophils metabolism, Nocodazole pharmacology, Peptide Fragments genetics, Peptide Fragments physiology, Protein Structure, Tertiary genetics, Protein Structure, Tertiary physiology, Receptors, Interleukin-8A antagonists & inhibitors, Receptors, Interleukin-8A blood, Receptors, Interleukin-8A genetics, Receptors, Interleukin-8B antagonists & inhibitors, Receptors, Interleukin-8B blood, Receptors, Interleukin-8B genetics, Transfection, Actins physiology, Receptors, Interleukin-8A metabolism, Receptors, Interleukin-8B metabolism
- Abstract
The ligand-induced internalization and recycling of chemokine receptors play a significant role in their regulation. In this study, we analyzed the involvement of actin filaments and of microtubules in the control of ligand-induced internalization and recycling of CXC chemokine receptor (CXCR)1 and CXCR2, two closely related G protein-coupled receptors that mediate ELR-expressing CXC chemokine-induced cellular responses. Nocodazole, a microtubule-disrupting agent, did not affect the IL-8-induced reduction in cell surface expression of CXCR1 and CXCR2, nor did it affect the recycling of these receptors following ligand removal and cell recovery at 37 degrees C. In contrast, cytochalasin D, an actin filament depolymerizing agent, promoted the IL-8-induced reduction in cell surface expression of both CXCR1 and CXCR2. Cytochalasin D significantly inhibited the recycling of both CXCR1 and CXCR2 following IL-8-induced internalization, the inhibition being more pronounced for CXCR2 than for CXCR1. Potent inhibition of recycling was observed also when internalization of CXCR2 was induced by another ELR-expressing CXC chemokine, granulocyte chemotactic protein-2. By the use of carboxyl terminus-truncated CXCR1 and CXCR2 it was observed that the carboxyl terminus domains of CXCR1 and CXCR2 were partially involved in the regulation of the actin-mediated process of receptor recycling. The cytochalasin D-mediated inhibition of CXCR2 recycling had a functional relevance because it impaired the ability of CXCR2-expressing cells to mediate cellular responses. These results suggest that actin filaments, but not microtubules, are involved in the regulation of the intracellular trafficking of CXCR1 and CXCR2, and that actin filaments may be required to enable cellular resensitization following a desensitized refractory period.
- Published
- 2001
- Full Text
- View/download PDF
11. GCP-2-induced internalization of IL-8 receptors: hierarchical relationships between GCP-2 and other ELR(+)-CXC chemokines and mechanisms regulating CXCR2 internalization and recycling.
- Author
-
Feniger-Barish R, Belkin D, Zaslaver A, Gal S, Dori M, Ran M, and Ben-Baruch A
- Subjects
- Androstadienes pharmacology, Antigens, CD genetics, Cell Line, Chemokine CXCL6, Chemokines, CXC genetics, Enzyme Inhibitors pharmacology, Heterotrimeric GTP-Binding Proteins physiology, Humans, Kidney, Peptides pharmacology, Pertussis Toxin, Phosphorylation drug effects, Protein Processing, Post-Translational drug effects, Protein-Tyrosine Kinases antagonists & inhibitors, Protein-Tyrosine Kinases physiology, Receptors, Chemokine genetics, Receptors, Interleukin genetics, Receptors, Interleukin-8A, Receptors, Interleukin-8B, Recombinant Fusion Proteins physiology, Transfection, Virulence Factors, Bordetella pharmacology, Wortmannin, beta-Thromboglobulin, Antigens, CD biosynthesis, Antigens, CD metabolism, Chemokines, CXC physiology, Chemotaxis physiology, Down-Regulation drug effects, Endocytosis physiology, Receptors, Chemokine biosynthesis, Receptors, Interleukin biosynthesis, Receptors, Interleukin metabolism, Signal Transduction
- Abstract
The chemotactic potencies of ELR(+)-CXC chemokines during acute inflammation are regulated by their binding affinities and by their ability to activate, desensitize, and internalize their specific receptors, CXCR1 and CXCR2. To gain insight into the fine mechanisms that control acute inflammatory processes, we have focused in this study on the highly potent ELR(+)-CXC chemokine Granulocyte Chemotactic Protein 2 (GCP-2), and on its ability to control the cell surface expression of CXCR1 and CXCR2. Although GCP-2 has been considered an effective ligand for both CXCR1 and CXCR2, our findings demonstrated that it was a potent inducer of CXCR2 internalization only. A functional hierarchy was shown to exist between GCP-2 and 2 other ELR(+)-CXC chemokines, IL-8 and NAP-2, in their abilities to induce CXCR1 and CXCR2 internalization, according to the following: IL-8 > GCP-2 > NAP-2. By the use of pertussis toxin (PTx), it was demonstrated that the actual events of G(alphai)-coupling to CXCR2 do not have a major role in the regulation of its internalization. Rather, CXCR2 internalization was shown to be negatively controlled by induction of signaling events, as indicated by the promotion of CXCR2 internalization following exposure to wortmannin, a potent inhibitor of phosphatidylinositol (PI) 3 kinases and PI4 kinases. Furthermore, our results suggest that rab11(+)-endosomes participate in the trafficking of CXCR2 through the endocytic pathway, to eventually allow its recycling back to the plasma membrane. To conclude, our findings shed light on the interrelationships between GCP-2 and other ELR(+)-CXC chemokines, and determine the mechanisms involved in the regulation of GCP-2-induced internalization and recycling of CXCR2. (Blood. 2000;95:1551-1559)
- Published
- 2000
12. Differential modes of regulation of cxc chemokine-induced internalization and recycling of human CXCR1 and CXCR2.
- Author
-
Feniger-Barish R, Ran M, Zaslaver A, and Ben-Baruch A
- Subjects
- Amino Acid Sequence, Humans, Molecular Sequence Data, Phosphorylation, Receptors, Interleukin-8A, Receptors, Interleukin-8B, Antigens, CD physiology, Chemokines, CXC physiology, Neutrophils physiology, Receptors, Chemokine physiology, Receptors, Interleukin physiology, Signal Transduction
- Abstract
Studies of human neutrophil IL-8 receptors, CXCR1 and CXCR2, have shown that the two receptors are differentially regulated by ELR(+)-CXC chemokines, that they differ functionally and may have diverse roles in mediating the inflammatory process. To elucidate the role of CXCR1 and CXCR2 in inflammation and to delineate the basis for the divergent regulation of these receptors by IL-8 and NAP-2, we characterized the IL-8- and NAP-2-induced mechanisms regulating the expression of each receptor, focusing on receptor internalization and recycling. Using HEK 293 cell transfectants, IL-8 was shown to induce significantly higher levels of CXCR2 internalization than NAP-2. Moreover, although CXCR2 bound IL-8 and NAP-2 with similarly high affinity, IL-8 functionally competed with and displaced NAP-2, and prompted high levels of internalization, similar to those induced by IL-8 alone. In a system providing an identical cellular milieu for reliable comparisons between CXCR1 and CXCR2, we have shown that the mechanisms controlling the internalization of CXCR1 diverge from those regulating CXCR2 internalization. Whereas IL-8-induced internalization of CXCR1 was profoundly dependent on a region of the carboxyl terminus expressing six phosphorylation sites, internalization of CXCR2 was primarily regulated by a membrane proximal domain of the carboxyl terminus that does not express phosphorylation sites. Analysis of receptor re-expression on the plasma membrane indicated that at early time points following removal of free ligand and incubation of the cells at 37 degrees C, receptor recycling accounted for recovery of CXCR1 and CXCR2 expression, whereas at later time points other processes may be involved in receptor re-expression. Phosphorylation-independent mechanisms were shown to direct both receptors to the recycling pathway. The differential control of CXCR1 vs CXCR2 internalization by IL-8 and NAP-2, as well as by phosphorylation-mediated mechanisms, suggests that a chemokine- and receptor-specific mode of regulation of internalization may contribute to the divergent activities of these receptors., (Copyright 1999 Academic Press.)
- Published
- 1999
- Full Text
- View/download PDF
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.