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Article: Impact of Aging on the Frequency, Phenotype, and Function of CD161-Expressing T Cells.

van der Geest, Kornelis S M / Kroesen, Bart-Jan / Horst, Gerda / Abdulahad, Wayel H / Brouwer, Elisabeth / Boots, Annemieke M H

Frontiers in immunology

2018 Volume 9, Page(s) 752

Abstract: Immune-aging is associated with perturbed immune responses in the elderly. CD161-expressing T cells, i.e., the previously described subsets of ... ...

Abstract	Immune-aging is associated with perturbed immune responses in the elderly. CD161-expressing T cells, i.e., the previously described subsets of CD161
MeSH term(s)	Adult ; Aged ; Aged, 80 and over ; Aging/immunology ; Female ; Humans ; Male ; Middle Aged ; NK Cell Lectin-Like Receptor Subfamily B/immunology ; Phenotype ; T-Lymphocytes/immunology ; Young Adult
Chemical Substances	KLRB1 protein, human ; NK Cell Lectin-Like Receptor Subfamily B
Language	English
Publishing date	2018-04-19
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2606827-8
ISSN	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2018.00752
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Article ; Online: Lack of IL-17 Receptor A signaling aggravates lymphoproliferation in C57BL/6 lpr mice.

Corneth, Odilia B J / Schaper, Fleur / Luk, Franka / Asmawidjaja, Patrick S / Mus, Adriana M C / Horst, Gerda / Heeringa, Peter / Hendriks, Rudi W / Westra, Johanna / Lubberts, Erik

Scientific reports

2019 Volume 9, Issue 1, Page(s) 4032

Abstract: Defects in Fas function correlate with susceptibility to systemic autoimmune diseases like autoimmune lymphoproliferative syndrome (ALPS) and systemic lupus erythematosus (SLE). C57BL/6 lpr (B6/lpr) mice are used as an animal model of ALPS and develop a ... ...

Abstract	Defects in Fas function correlate with susceptibility to systemic autoimmune diseases like autoimmune lymphoproliferative syndrome (ALPS) and systemic lupus erythematosus (SLE). C57BL/6 lpr (B6/lpr) mice are used as an animal model of ALPS and develop a mild SLE phenotype. Involvement of interleukin-17A (IL-17A) has been suggested in both phenotypes. Since IL-17 receptor A is part of the signaling pathway of many IL-17 family members we investigated the role of IL-17 receptor signaling in disease development in mice with a B6/lpr background. B6/lpr mice were crossed with IL-17 receptor A deficient (IL-17RA KO) mice and followed over time for disease development. IL-17RA KO/lpr mice presented with significantly enhanced lymphoproliferation compared with B6/lpr mice, which was characterized by dramatic lymphadenomegaly/splenomegaly and increased lymphocyte numbers, expansion of double-negative (DN) T-cells and enhanced plasma cell formation. However, the SLE phenotype was not enhanced, as anti-nuclear antibody (ANA) titers and induction of glomerulonephritis were not different. In contrast, levels of High Mobility Group Box 1 (HMGB1) and anti-HMGB1 autoantibodies were significantly increased in IL-17RA KO/lpr mice compared to B6/lpr mice. These data show that lack of IL-17RA signaling aggravates the lymphoproliferative phenotype in B6/lpr mice but does not affect the SLE phenotype.
MeSH term(s)	Animals ; Autoimmune Lymphoproliferative Syndrome/immunology ; B-Lymphocytes/immunology ; B-Lymphocytes/pathology ; Cell Proliferation ; HMGB1 Protein/metabolism ; Kidney/immunology ; Kidney/pathology ; Lupus Erythematosus, Systemic/immunology ; Lymph Nodes/immunology ; Lymph Nodes/pathology ; Mice ; Mice, Inbred C57BL ; Mice, Inbred MRL lpr ; Mice, Knockout ; Receptors, Interleukin-17/genetics ; Receptors, Interleukin-17/physiology ; Spleen/immunology ; Spleen/pathology ; T-Lymphocytes/immunology ; T-Lymphocytes/pathology
Chemical Substances	HMGB1 Protein ; HMGB1 protein, mouse ; Il17ra protein, mouse ; Receptors, Interleukin-17
Language	English
Publishing date	2019-03-11
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-019-39483-w
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Article ; Online: Treatment with Anti-HMGB1 Monoclonal Antibody Does Not Affect Lupus Nephritis in MRL/lpr Mice.

Schaper, Fleur / van Timmeren, Mirjan M / Petersen, Arjen / Horst, Gerda / Bijl, Marc / Limburg, Pieter C / Westra, Johanna / Heeringa, Peter

Molecular medicine (Cambridge, Mass.)

2016 Volume 22, Page(s) 12–21

Abstract: High mobility group box 1 (HMGB1) is a nuclear DNA binding protein that acts as an alarmin when secreted. HMGB1 is increased in systemic lupus erythematosus and might represent a potential therapeutic target. We investigated whether treatment with an ... ...

Abstract	High mobility group box 1 (HMGB1) is a nuclear DNA binding protein that acts as an alarmin when secreted. HMGB1 is increased in systemic lupus erythematosus and might represent a potential therapeutic target. We investigated whether treatment with an anti-HMGB1 antibody affects the development of lupus nephritis in MRL/lpr mice. Seven-week-old MRL/lpr mice were injected intraperitoneally twice weekly for 10 wks with 50 μg monoclonal anti-HMGB1 (2G7, mouse IgG2b) (n = 12) or control antibody (n = 11). Control MRL/MPJ mice (n = 10) were left untreated. Every 2 wks, blood was drawn and urine was collected at wk 7, 11 and 17. Mice were sacrificed at 17 wks for complete disease evaluation. Plasma HMGB1 and anti-HMGB1 levels were increased in MRL/lpr mice compared with control MRL/MPJ mice. There were no differences in albuminuria, urine HMGB1 and plasma levels of complement C3, anti-dsDNA and proinflammatory cytokines between untreated and treated mice at any time point. Lupus nephritis of mice treated with anti-HMGB1 monoclonal antibody (mAb) was classified as class III (n = 3) and class IV (n = 9), while mice treated with control mAb were classified as class II (n = 4), class III (n = 2) and class IV (n = 5). IgG and C3 deposits in kidneys were similar in mice treated with anti-HMGB1 mAb or control mAb. In conclusion, treatment with monoclonal anti-HMGB-1 antibody 2G7 does not affect development of lupus nephritis, disease progression or proinflammatory cytokine levels in MRL/lpr mice. This result indicates that blocking of HMGB1 by this neutralizing antibody does not affect lupus nephritis in MRL/lpr mice.
Language	English
Publishing date	2016-01-13
Publishing country	England
Document type	Journal Article
ZDB-ID	1283676-x
ISSN	1528-3658 ; 1076-1551
ISSN (online)	1528-3658
ISSN	1076-1551
DOI	10.2119/molmed.2015.00176
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Article ; Online: High mobility group box 1 skews macrophage polarization and negatively influences phagocytosis of apoptotic cells.

Schaper, Fleur / de Leeuw, Karina / Horst, Gerda / Bootsma, Hendrika / Limburg, Pieter C / Heeringa, Peter / Bijl, Marc / Westra, Johanna

Rheumatology (Oxford, England)

2016 Volume 55, Issue 12, Page(s) 2260–2270

Abstract: Objectives: Decreased phagocytosis of apoptotic cells plays an important role in the pathogenesis of SLE. This can lead to secondary necrosis and release of nuclear proteins, such as high mobility group box 1 (HMGB1). We hypothesized that increased ... ...

Abstract	Objectives: Decreased phagocytosis of apoptotic cells plays an important role in the pathogenesis of SLE. This can lead to secondary necrosis and release of nuclear proteins, such as high mobility group box 1 (HMGB1). We hypothesized that increased HMGB1 levels, as present in SLE, skew macrophage differentiation towards M1-like phenotypes and thereby diminish uptake of apoptotic cells. The aim of this study was to investigate the effect of HMGB1 on macrophage polarization and on phagocytic capacity of differentiated macrophages. Methods: SLE patients with quiescent disease (SLEDAI ⩽4) and healthy controls (HCs) were included. Monocytes and differentiated M1 and M2 macrophages were assessed for expression of M1 and M2 markers and for phagocytic capacity. HMGB1 was added during differentiation and during phagocytosis. Results: Expression of CD86 (M1) was not different, whereas CD163 (M2) was significantly lower on SLE monocytes. After differentiation, no differences regarding surface receptor expression and phagocytic capacity were observed between M1 and M2 macrophages from SLE patients and HCs. Addition of HMGB1 during M2 differentiation resulted in high IL-6 and TNF-α mRNA expression and reduced phagocytic capacity of apoptotic cells. Furthermore, adding HMGB1 to apoptotic Jurkat cells diminished phagocytosis of these cells. Conclusion: Circulating monocytes from SLE patients display an M1-like phenotype compared with HCs, but in vitro differentiation abolishes this difference. HMGB1 skews differentiation of M2-like macrophages towards an M1-like phenotype and, subsequently, reduces phagocytosis of apoptotic cells. These data imply that the phenotype of monocytes or macrophages is determined by their environment, such as the presence of cytokines and HMGB1.
MeSH term(s)	Adult ; Apoptosis/physiology ; Biomarkers/metabolism ; Cell Differentiation/physiology ; Female ; HMGB1 Protein/pharmacology ; HMGB1 Protein/physiology ; Humans ; In Vitro Techniques ; Jurkat Cells/physiology ; Leukocytes, Mononuclear/physiology ; Macrophage Activation/physiology ; Macrophages/physiology ; Male ; Middle Aged ; Necrosis ; Phagocytosis/drug effects ; Phagocytosis/physiology ; RNA, Messenger/metabolism ; Young Adult
Chemical Substances	Biomarkers ; HMGB1 Protein ; RNA, Messenger
Language	English
Publishing date	2016-12
Publishing country	England
Document type	Journal Article
ZDB-ID	1464822-2
ISSN	1462-0332 ; 1462-0324
ISSN (online)	1462-0332
ISSN	1462-0324
DOI	10.1093/rheumatology/kew324
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Article ; Online: The CD27 and CD70 costimulatory pathway inhibits effector function of T helper 17 cells and attenuates associated autoimmunity.

Coquet, Jonathan M / Middendorp, Sabine / van der Horst, Gerda / Kind, Jop / Veraar, Elise A M / Xiao, Yanling / Jacobs, Heinz / Borst, Jannie

Immunity

2013 Volume 38, Issue 1, Page(s) 53–65

Abstract: T helper 17 (Th17) cells protect against infection but also promote inflammation and autoimmunity. Therefore, the factors that govern Th17 cell differentiation are of special interest. The CD27 and CD70 costimulatory pathway impeded Th17 effector cell ... ...

Abstract	T helper 17 (Th17) cells protect against infection but also promote inflammation and autoimmunity. Therefore, the factors that govern Th17 cell differentiation are of special interest. The CD27 and CD70 costimulatory pathway impeded Th17 effector cell differentiation and associated autoimmunity in a mouse model of multiple sclerosis. CD27 or CD70 deficiency exacerbated disease, whereas constitutive CD27 signaling strongly reduced disease incidence and severity. CD27 signaling did not impact master regulators of T helper cell lineage commitment but selectively repressed transcription of the key effector molecules interleukin-17 (IL-17) and the chemokine receptor CCR6 in differentiating Th17 cells. CD27 mediated this repression at least in part via the c-Jun N-terminal kinase (JNK) pathway that restrained IL-17 and CCR6 expression in differentiating Th17 cells. CD27 signaling also resulted in epigenetic silencing of the Il17a gene. Thus, CD27 costimulation via JNK signaling, transcriptional, and epigenetic effects suppresses Th17 effector cell function and associated pathological consequences.
MeSH term(s)	Animals ; Autoimmunity/genetics ; Autoimmunity/immunology ; CD27 Ligand/genetics ; CD27 Ligand/metabolism ; Cell Differentiation/immunology ; Encephalomyelitis, Autoimmune, Experimental/genetics ; Encephalomyelitis, Autoimmune, Experimental/immunology ; Encephalomyelitis, Autoimmune, Experimental/metabolism ; Epigenesis, Genetic ; Gene Expression Regulation ; Gene Silencing ; Interleukin-17/genetics ; Interleukin-17/immunology ; Interleukin-17/metabolism ; MAP Kinase Signaling System ; Mice ; Mice, Transgenic ; Nuclear Receptor Subfamily 1, Group F, Member 3/genetics ; Nuclear Receptor Subfamily 1, Group F, Member 3/metabolism ; Receptors, CCR6/genetics ; Receptors, CCR6/metabolism ; Signal Transduction ; Th17 Cells/cytology ; Th17 Cells/immunology ; Th17 Cells/metabolism ; Tumor Necrosis Factor Receptor Superfamily, Member 7/metabolism
Chemical Substances	CD27 Ligand ; Interleukin-17 ; Nuclear Receptor Subfamily 1, Group F, Member 3 ; Receptors, CCR6 ; Tumor Necrosis Factor Receptor Superfamily, Member 7
Language	English
Publishing date	2013-01-24
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1217235-2
ISSN	1097-4180 ; 1074-7613
ISSN (online)	1097-4180
ISSN	1074-7613
DOI	10.1016/j.immuni.2012.09.009
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Zs.A 4227: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
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Article ; Online: Aging-dependent decline of IL-10 producing B cells coincides with production of antinuclear antibodies but not rheumatoid factors.

van der Geest, Kornelis S M / Lorencetti, Pedro G / Abdulahad, Wayel H / Horst, Gerda / Huitema, Minke / Roozendaal, Caroline / Kroesen, Bart-Jan / Brouwer, Elisabeth / Boots, Annemieke M H

Experimental gerontology

2016 Volume 75, Page(s) 24–29

Abstract: Aging is associated with development of autoimmunity. Loss of B cell tolerance in the elderly is suggested by an increased prevalence of anti-nuclear antibodies (ANAs) and rheumatoid factors (RFs). Accumulating evidence indicates that B cells also impact ...

Abstract	Aging is associated with development of autoimmunity. Loss of B cell tolerance in the elderly is suggested by an increased prevalence of anti-nuclear antibodies (ANAs) and rheumatoid factors (RFs). Accumulating evidence indicates that B cells also impact autoimmunity via secretion of cytokines. So far, few studies have directly assessed the effect of aging on the latter B cell function. Here, we determined if and how human aging influences the production of cytokines by B cells. In a cross-sectional study, we found that absolute numbers of circulating B cells were similar in 31 young (ages 19-39) and 73 old (age ≥ 60) individuals. Numbers of transitional B cells (CD19(+)CD27(-)CD38(High)CD24(High)) were decreased in old individuals, whereas numbers of naive and memory B cell subsets were comparable in young and old individuals. Short-term in vitro stimulation of whole blood samples revealed that numbers of B cells capable of producing TNF-α were similar in young and old individuals. In contrast, B cells capable of IL-10 production were decreased in old subjects. This decline of IL-10(+) B cells was observed in old individuals that were ANA positive, and in those that were negative for both ANAs and RFs. However, IL-10(+) B cells were remarkably well retained in the circulation of old subjects that were RF positive. Thus, pro-inflammatory TNF-α(+) B cells are retained in the elderly, whereas IL-10(+) B cells generally decline. In addition, our findings indicate that IL-10(+) B cells may differentially impact the development of ANAs and RFs in the elderly.
MeSH term(s)	Adult ; Aged ; Aged, 80 and over ; Aging/immunology ; Antibodies, Antinuclear/biosynthesis ; B-Lymphocyte Subsets/immunology ; B-Lymphocytes/immunology ; Female ; Humans ; Interleukin-10/biosynthesis ; Lymphocyte Count ; Male ; Middle Aged ; Rheumatoid Factor/biosynthesis ; Tumor Necrosis Factor-alpha/biosynthesis ; Young Adult
Chemical Substances	Antibodies, Antinuclear ; IL10 protein, human ; Tumor Necrosis Factor-alpha ; Interleukin-10 (130068-27-8) ; Rheumatoid Factor (9009-79-4)
Language	English
Publishing date	2016-03
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	390992-x
ISSN	1873-6815 ; 0531-5565
ISSN (online)	1873-6815
ISSN	0531-5565
DOI	10.1016/j.exger.2015.12.009
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Article ; Online: Quantifying Distribution of Flow Cytometric TCR-Vβ Usage with Economic Statistics.

van der Geest, Kornelis S M / Abdulahad, Wayel H / Horst, Gerda / Lorencetti, Pedro G / Bijzet, Johan / Arends, Suzanne / van der Heiden, Marieke / Buisman, Anne-Marie / Kroesen, Bart-Jan / Brouwer, Elisabeth / Boots, Annemieke M H

PloS one

2015 Volume 10, Issue 4, Page(s) e0125373

Abstract: Measuring changes of the T cell receptor (TCR) repertoire is important to many fields of medicine. Flow cytometry is a popular technique to study the TCR repertoire, as it quickly provides insight into the TCR-Vβ usage among well-defined populations of T ...

Abstract	Measuring changes of the T cell receptor (TCR) repertoire is important to many fields of medicine. Flow cytometry is a popular technique to study the TCR repertoire, as it quickly provides insight into the TCR-Vβ usage among well-defined populations of T cells. However, the interpretation of the flow cytometric data remains difficult, and subtle TCR repertoire changes may go undetected. Here, we introduce a novel means for analyzing the flow cytometric data on TCR-Vβ usage. By applying economic statistics, we calculated the Gini-TCR skewing index from the flow cytometric TCR-Vβ analysis. The Gini-TCR skewing index, which is a direct measure of TCR-Vβ distribution among T cells, allowed us to track subtle changes of the TCR repertoire among distinct populations of T cells. Application of the Gini-TCR skewing index to the flow cytometric TCR-Vβ analysis will greatly help to gain better understanding of the TCR repertoire in health and disease.
MeSH term(s)	CD4-Positive T-Lymphocytes/immunology ; CD8-Positive T-Lymphocytes/immunology ; Cell Differentiation/immunology ; Flow Cytometry/statistics & numerical data ; Humans ; Immunization ; Receptors, Antigen, T-Cell, alpha-beta/immunology ; Receptors, Antigen, T-Cell, alpha-beta/isolation & purification ; T-Lymphocytes, Cytotoxic/immunology ; T-Lymphocytes, Helper-Inducer/immunology ; Vaccination
Chemical Substances	Receptors, Antigen, T-Cell, alpha-beta
Language	English
Publishing date	2015
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	1932-6203
ISSN (online)	1932-6203
DOI	10.1371/journal.pone.0125373
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Article ; Online: Serum markers associated with disease activity in giant cell arteritis and polymyalgia rheumatica.

van der Geest, Kornelis S M / Abdulahad, Wayel H / Rutgers, Abraham / Horst, Gerda / Bijzet, Johan / Arends, Suzanne / Roffel, Mirjam P / Boots, Annemieke M H / Brouwer, Elisabeth

Rheumatology (Oxford, England)

2015 Volume 54, Issue 8, Page(s) 1397–1402

Abstract: Objective: To compare multiple serum markers for their ability to detect active disease in patients with GCA and in those with PMR.: Methods: Twenty-six markers related to immune cells that may be involved in GCA and PMR were determined by ELISA and ... ...

Abstract	Objective: To compare multiple serum markers for their ability to detect active disease in patients with GCA and in those with PMR. Methods: Twenty-six markers related to immune cells that may be involved in GCA and PMR were determined by ELISA and multiplex assay in the serum of 24 newly diagnosed, untreated GCA/PMR patients, 14 corticosteroid (CS)-treated GCA/PMR patients in remission and 13 healthy controls. Receiver operating characteristic analysis with area under the curve and Spearman's correlation coefficients were performed. Results: Serum B-cell activating factor (BAFF), CXCL9 and IL-6 were increased in newly diagnosed GCA and PMR patients. Serum CCL2, CCL11, IL-10 and sIL-2R were modulated in GCA patients only and CXCL10 in PMR patients only. BAFF, CXCL9 and IL-6 accurately distinguished newly diagnosed GCA and PMR patients from healthy controls, as shown by area under the curve > 0.80. Upon CS-induced remission, serum BAFF and IL-6 decreased significantly in both GCA and PMR patients, whereas CXCL9 remained high. Serum BAFF and IL-6 correlated strongly with ESR and CRP in GCA and PMR patients. Conclusion: Among the serum markers tested, BAFF and IL-6 showed the strongest association with disease activity in both GCA and PMR patients. The diagnostic value of these markers should be evaluated in larger, longitudinal studies with GCA and PMR patients, and in patients with infections or other inflammatory conditions.
MeSH term(s)	Aged ; B-Cell Activating Factor/blood ; Biomarkers/blood ; Blood Sedimentation ; C-Reactive Protein/metabolism ; Case-Control Studies ; Chemokine CXCL9/blood ; Female ; Giant Cell Arteritis/blood ; Giant Cell Arteritis/diagnosis ; Humans ; Interleukin-6/blood ; Male ; Middle Aged ; Polymyalgia Rheumatica/blood ; Polymyalgia Rheumatica/diagnosis ; Predictive Value of Tests ; Severity of Illness Index
Chemical Substances	B-Cell Activating Factor ; Biomarkers ; CXCL9 protein, human ; Chemokine CXCL9 ; Interleukin-6 ; TNFSF13B protein, human ; C-Reactive Protein (9007-41-4)
Language	English
Publishing date	2015-08
Publishing country	England
Document type	Comparative Study ; Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1464822-2
ISSN	1462-0332 ; 1462-0324
ISSN (online)	1462-0332
ISSN	1462-0324
DOI	10.1093/rheumatology/keu526
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Article: Ubiquitin ligase activity of c-Cbl guides the epidermal growth factor receptor into clathrin-coated pits by two distinct modes of Eps15 recruitment.

de Melker, Annemieke A / van der Horst, Gerda / Borst, Jannie

The Journal of biological chemistry

2004 Volume 279, Issue 53, Page(s) 55465–55473

Abstract: We have demonstrated previously that c-Cbl requires the presence of a functional ubiquitin interacting motif (UIM) in Eps15 to mediate epidermal growth factor receptor (EGFR) endocytosis. Both the ubiquitin ligase activity of c-Cbl and the UIM of Eps15 ... ...

Abstract	We have demonstrated previously that c-Cbl requires the presence of a functional ubiquitin interacting motif (UIM) in Eps15 to mediate epidermal growth factor receptor (EGFR) endocytosis. Both the ubiquitin ligase activity of c-Cbl and the UIM of Eps15 were necessary for plasma membrane recruitment of Eps15 and entry of ligand-bound EGFR into coated pits and vesicles containing Eps15. This is consistent with a scenario in which ubiquitin moieties appended to activated EGFR complexes act as docking sites for Eps15 and thereby recruit receptors into clathrin coated pits. Here, we have investigated which additional structural features of c-Cbl are required for this process. We find that c-Cbl can guide ligand-bound EGFR into the Eps15 internalization route by two distinct mechanisms. These are either dependent on the phosphotyrosine binding domain of c-Cbl that directly binds to the EGFR or on the region C-terminal of the Ring finger, which allows for indirect binding to an alternative site on the receptor. No strict requirement exists for either ubiquitin modified EGFR or the Cbl binding ubiquitination substrate CIN85 as docking site for the UIM of Eps15. Only in the phosphotyrosine binding-dependent pathway, the EGFR is ubiquitinated and may serve as a site of recruitment for Eps15. Only in this pathway, Eps15 is tyrosine-phosphorylated, but this appears unrelated to its capacity to participate in EGFR internalization.
MeSH term(s)	Adaptor Proteins, Signal Transducing ; Animals ; Binding Sites ; CHO Cells ; COS Cells ; Calcium-Binding Proteins/metabolism ; Cell Membrane/metabolism ; Clathrin-Coated Vesicles/metabolism ; Cricetinae ; DNA, Complementary/metabolism ; ErbB Receptors/metabolism ; Genetic Vectors ; Humans ; Immunoblotting ; Immunoprecipitation ; Intracellular Signaling Peptides and Proteins ; Ligands ; Mice ; Microscopy, Fluorescence ; Models, Biological ; Models, Genetic ; Mutation ; Phosphoproteins/metabolism ; Phosphorylation ; Point Mutation ; Protein Binding ; Protein Structure, Tertiary ; Proto-Oncogene Proteins/metabolism ; Proto-Oncogene Proteins c-cbl ; Structure-Activity Relationship ; Time Factors ; Transfection ; Tyrosine/chemistry ; Ubiquitin/chemistry ; Ubiquitin/metabolism ; Ubiquitin-Protein Ligases/metabolism
Chemical Substances	Adaptor Proteins, Signal Transducing ; Calcium-Binding Proteins ; DNA, Complementary ; EPS15 protein, human ; Intracellular Signaling Peptides and Proteins ; Ligands ; Phosphoproteins ; Proto-Oncogene Proteins ; Ubiquitin ; Tyrosine (42HK56048U) ; Proto-Oncogene Proteins c-cbl (EC 2.3.2.27) ; Ubiquitin-Protein Ligases (EC 2.3.2.27) ; ErbB Receptors (EC 2.7.10.1) ; Cbl protein, mouse (EC 6.3.2.-)
Language	English
Publishing date	2004-10-01
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
DOI	10.1074/jbc.M409765200
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Article: c-Cbl directs EGF receptors into an endocytic pathway that involves the ubiquitin-interacting motif of Eps15.

de Melker, Annemieke A / van der Horst, Gerda / Borst, Jannie

Journal of cell science

2004 Volume 117, Issue Pt 21, Page(s) 5001–5012

Abstract: c-Cbl associates with the activated EGF receptor before endocytosis. We here reveal that the capacity of c-Cbl to promote receptor internalization depends on its ubiquitin ligase activity, which functionally connects the EGF receptor to Eps15, a mediator ...

Abstract	c-Cbl associates with the activated EGF receptor before endocytosis. We here reveal that the capacity of c-Cbl to promote receptor internalization depends on its ubiquitin ligase activity, which functionally connects the EGF receptor to Eps15, a mediator of clathrin-coated pit formation. EGF-induced phosphorylation of Eps15, as well as recruitment of Eps15 to the plasma membrane and its co-localization with the EGF receptor in endosomes required the ubiquitin ligase activity of c-Cbl. This suggested that ubiquitin provides a direct or indirect link between the receptor and Eps15. Indeed, EGF-induced redistribution of Eps15 to the plasma membrane and endosomes depended on its ubiquitin-interacting motif. Upon over-expression, the ubiquitin-interacting motif abrogated the capacity of c-Cbl to promote EGF receptor endocytosis and only allowed receptor internalization via a route that lacked Eps15. Our findings disclose a novel function for the c-Cbl ubiquitin ligase and identify ubiquitin as a module that directs the EGF receptor into an endocytic pathway involving Eps15.
MeSH term(s)	Adaptor Proteins, Signal Transducing ; Amino Acid Motifs ; Animals ; CHO Cells ; Calcium-Binding Proteins/chemistry ; Calcium-Binding Proteins/physiology ; Cell Membrane/metabolism ; Cricetinae ; Dose-Response Relationship, Drug ; Endocytosis ; Endosomes/metabolism ; Immunoblotting ; Immunoprecipitation ; Intracellular Signaling Peptides and Proteins ; Mice ; Microscopy, Fluorescence ; Phosphoproteins/chemistry ; Phosphoproteins/physiology ; Phosphorylation ; Protein Binding ; Protein Structure, Tertiary ; Proto-Oncogene Proteins/metabolism ; Proto-Oncogene Proteins/physiology ; Proto-Oncogene Proteins c-cbl ; Receptor, Epidermal Growth Factor/metabolism ; Time Factors ; Tyrosine/metabolism ; Ubiquitin/metabolism ; Ubiquitin-Protein Ligases/metabolism ; Ubiquitin-Protein Ligases/physiology
Chemical Substances	Adaptor Proteins, Signal Transducing ; Calcium-Binding Proteins ; Eps15 protein, mouse ; Intracellular Signaling Peptides and Proteins ; Phosphoproteins ; Proto-Oncogene Proteins ; Ubiquitin ; Tyrosine (42HK56048U) ; Proto-Oncogene Proteins c-cbl (EC 2.3.2.27) ; Ubiquitin-Protein Ligases (EC 2.3.2.27) ; Receptor, Epidermal Growth Factor (EC 2.7.10.1) ; Cbl protein, mouse (EC 6.3.2.-)
Language	English
Publishing date	2004-10-01
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2993-2
ISSN	1477-9137 ; 0021-9533
ISSN (online)	1477-9137
ISSN	0021-9533
DOI	10.1242/jcs.01354
Database	MEDical Literature Analysis and Retrieval System OnLINE

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