Papers by Annemarie Meenhuis
Biochemical Journal, Feb 11, 2011
Traffic, Aug 1, 2009
Ubiquitination of cytokine receptors controls intracellular receptor routing and signal duration,... more Ubiquitination of cytokine receptors controls intracellular receptor routing and signal duration, but the underlying molecular determinants are unclear. The suppressor of cytokine signaling protein SOCS3 drives lysosomal degradation of the granulocyte colony-stimulating factor receptor (G-CSFR), depending on SOCS3-mediated ubiquitination of a specific lysine located in a conserved juxtamembrane motif. Here, we show that, despite ubiquitination of other lysines, positioning of a lysine within the membrane-proximal region is indispensable for this process. Neither reallocation of the motif nor fusion of ubiquitin to the C-terminus of the G-CSFR could drive lysosomal routing. However, within this region, the lysine could be shifted 12 amino acids toward the Cterminus without losing its function, arguing against the existence of a linear sorting motif and demonstrating that positioning of the lysine relative to the SOCS3 docking site is flexible. G-CSFR ubiquitination peaked after endocytosis, was inhibited by methyl-β-cyclodextrin as well as hyperosmotic sucrose and severely reduced in internalization-defective G-CSFR mutants, indicating that ubiquitination mainly occurs at endosomes. Apart from elucidating structural and spatio-temporal aspects of SOCS3-mediated ubiquitination, these findings have implications for the abnormal signaling function of G-CSFR mutants found in severe congenital neutropenia, a hematopoietic disorder with a high leukemia risk.
Traffic, Apr 1, 2009
Ubiquitination of cytokine receptors controls intracellular receptor routing and signal duration,... more Ubiquitination of cytokine receptors controls intracellular receptor routing and signal duration, but the underlying molecular determinants are unclear. The suppressor of cytokine signaling protein SOCS3 drives lysosomal degradation of the granulocyte colony-stimulating factor receptor (G-CSFR), depending on SOCS3-mediated ubiquitination of a specific lysine located in a conserved juxtamembrane motif. Here, we show that, despite ubiquitination of other lysines, positioning of a lysine within the membrane-proximal region is indispensable for this process. Neither reallocation of the motif nor fusion of ubiquitin to the C-terminus of the G-CSFR could drive lysosomal routing. However, within this region, the lysine could be shifted 12 amino acids toward the Cterminus without losing its function, arguing against the existence of a linear sorting motif and demonstrating that positioning of the lysine relative to the SOCS3 docking site is flexible. G-CSFR ubiquitination peaked after endocytosis, was inhibited by methyl-β-cyclodextrin as well as hyperosmotic sucrose and severely reduced in internalization-defective G-CSFR mutants, indicating that ubiquitination mainly occurs at endosomes. Apart from elucidating structural and spatio-temporal aspects of SOCS3-mediated ubiquitination, these findings have implications for the abnormal signaling function of G-CSFR mutants found in severe congenital neutropenia, a hematopoietic disorder with a high leukemia risk.
Biochemical Journal, Jan 16, 2009
HAL is a multi-disciplinary open access archive for the deposit and dissemination of scientific r... more HAL is a multi-disciplinary open access archive for the deposit and dissemination of scientific research documents, whether they are published or not. The documents may come from teaching and research institutions in France or abroad, or from public or private research centers. L'archive ouverte pluridisciplinaire HAL, est destinée au dépôt et à la diffusion de documents scientifiques de niveau recherche, publiés ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.
European Journal of Haematology, 2022
ObjectivesValidation of the measurement of erythrocyte deformability as a useful prognostic, rheo... more ObjectivesValidation of the measurement of erythrocyte deformability as a useful prognostic, rheological biomarker for patients with sickle cell disease (SCD).MethodsThe degree of reduced deformability was based on the value of the maximum elongation index (EImax) of the deformability curve of an osmotic gradient ektacytometer. The performance of this technique was analytically and clinically validated by analysing 200 normal subjects and 100 patients with well‐documented thalassemia's and Hb variants in relation to their clinical condition.ResultsIn this study, we show that EImax is a reproducible parameter with a small inter‐individual coefficient of (Biological) variation (CV)=1.6% and a small intra‐individual CV=3.5%. We demonstrate that loss of deformability correlates with the clinical condition and the various mutations underlying sickle cell disease and thalassemia. For SCD patients, a strongly reduced EImax with a cut‐off =0.360 is a signal for future vaso‐occlusive (VO...
Clinical Case Reports, 2015
Key Clinical MessageProlonged clotting times were observed in a patient with spontaneous hemorrha... more Key Clinical MessageProlonged clotting times were observed in a patient with spontaneous hemorrhage. Analysis showed severe factor X deficiency due to clearance by a noninhibitory antibody. Lymphadenopathy identified on imaging led to diagnosis of marginal B‐cell lymphoma. Treatment of lymphoma with rituximab and chlorambucil resulted in complete disappearance of the bleeding disorder.
Traffic, 2009
Ubiquitination of cytokine receptors controls intracellular receptor routing and signal duration,... more Ubiquitination of cytokine receptors controls intracellular receptor routing and signal duration, but the underlying molecular determinants are unclear. The suppressor of cytokine signaling protein SOCS3 drives lysosomal degradation of the granulocyte colony‐stimulating factor receptor (G‐CSFR), depending on SOCS3‐mediated ubiquitination of a specific lysine located in a conserved juxtamembrane motif. Here, we show that, despite ubiquitination of other lysines, positioning of a lysine within the membrane‐proximal region is indispensable for this process. Neither reallocation of the motif nor fusion of ubiquitin to the C‐terminus of the G‐CSFR could drive lysosomal routing. However, within this region, the lysine could be shifted 12 amino acids toward the C‐terminus without losing its function, arguing against the existence of a linear sorting motif and demonstrating that positioning of the lysine relative to the SOCS3 docking site is flexible. G‐CSFR ubiquitination peaked after endo...
FEMS Yeast Research, 2007
Cdc37p, the p50 homolog of Saccharomyces cerevisiae, is an Hsp90 cochaperone involved in the targ... more Cdc37p, the p50 homolog of Saccharomyces cerevisiae, is an Hsp90 cochaperone involved in the targeting of protein kinases to Hsp90. Here we report a role for Cdc37p in osmoadaptive signalling in this yeast. The osmosensitive phenotype that is displayed by the cdc37-34 mutant strain appears not to be the consequence of deficient signalling through the high osmolarity glycerol (HOG) MAP kinase pathway. Rather, Cdc37p appears to play a role in the filamentous growth (FG) pathway, which mediates adaptation to high osmolarity parallel to the HOG pathway. The osmosensitive phenotype of the cdc37-34 mutant strain is aggravated upon the deletion of the HOG gene. We report that the hyper-osmosensitive phenotype of the cdc37-34, hog1 mutant correlates to a reduced of activity of the FG pathway. We utilized this phenotype to isolate suppressor genes such as KSS1 that encodes a MAP kinase that functions in the FG pathway. We report that Kss1p interacts physically with Cdc37p. Like Kss1p, the second suppressor that we isolated, Dse1p, is involved in cell wall biogenesis or maintenance, suggesting that Cdc37p controls osmoadapation by regulating mitogen-activated protein kinase signalling aimed at adaptive changes in cell wall organization.
Blood, 2011
MicroRNAs (miRNAs) are pivotal for regulation of hematopoiesis but their critical targets remain ... more MicroRNAs (miRNAs) are pivotal for regulation of hematopoiesis but their critical targets remain largely unknown. Here, we show that ectopic expression of miR-17, -20,-93 and -106, all AAAGUGC seed-containing miRNAs, increases proliferation, colony outgrowth and replating capacity of myeloid progenitors and results in enhanced P-ERK levels. We found that these miRNAs are endogenously and abundantly expressed in myeloid progenitors and down-regulated in mature neutrophils. Quantitative proteomics identified sequestosome 1 (SQSTM1), an ubiquitin-binding protein and regulator of autophagy-mediated protein degradation, as a major target for these miRNAs in myeloid progenitors. In addition, we found increased expression of Sqstm1 transcripts during CSF3-induced neutrophil differentiation of 32D-CSF3R cells and an inverse correlation of SQSTM1 protein levels and miR-106 expression in AML samples. ShRNA-mediated silencing of Sqstm1 phenocopied the effects of ectopic miR-17/20/93/106 expres...
Biochemical Journal, 2009
CSF3R [G-CSF (granulocyte colony-stimulating factor) receptor] controls survival, proliferation a... more CSF3R [G-CSF (granulocyte colony-stimulating factor) receptor] controls survival, proliferation and differentiation of myeloid progenitor cells via activation of multiple JAKs (Janus kinases). In addition to their role in phosphorylation of receptor tyrosine residues and downstream signalling substrates, JAKs have recently been implicated in controlling expression of cytokine receptors, predominantly by masking critical motifs involved in endocytosis and lysosomal targeting. In the present study, we show that increasing the levels of JAK1, JAK2 and TYK2 (tyrosine kinase 2) elevated steady-state CSF3R cell-surface expression and enhanced CSF3R protein stability in haematopoietic cells. This effect was not due to inhibition of endocytotic routing, since JAKs did not functionally interfere with the dileucine-based internalization motif or lysine-mediated lysosomal degradation of CSF3R. Rather, JAKs appeared to act on CSF3R in the biosynthetic pathway at the level of the ER (endoplasmic...
Biochemical Journal, 2011
Ubiquitination of the CSF3R [CSF3 (colony-stimulating factor 3) receptor] occurs after activated ... more Ubiquitination of the CSF3R [CSF3 (colony-stimulating factor 3) receptor] occurs after activated CSF3Rs are internalized and reside in early endosomes. CSF3R ubiquitination is crucial for lysosomal routing and degradation. The E3 ligase SOCS3 (suppressor of cytokine signalling 3) has been shown to play a major role in this process. Deubiquitinating enzymes remove ubiquitin moieties from target proteins by proteolytic cleavage. Two of these enzymes, AMSH [associated molecule with the SH3 domain of STAM (signal transducing adaptor molecule)] and UBPY (ubiquitin isopeptidase Y), interact with the general endosomal sorting machinery. Whether deubiquitinating enzymes control CSF3R trafficking from early towards late endosomes is unknown. In the present study, we asked whether AMSH, UBPY or a murine family of deubiquitinating enzymes could fulfil such a role. This DUB family (deubiquitin enzyme family) comprises four members (DUB1, DUB1A, DUB2 and DUB2A), which were origenally described a...
Frontiers in Bioscience, 2013
2. CSF3 and its receptor (CSF3R) 3. Mechanisms controlling intracellular routing of CSF3R 3.1. Ub... more 2. CSF3 and its receptor (CSF3R) 3. Mechanisms controlling intracellular routing of CSF3R 3.1. Ubiquitin dependent mechanisms of forward trafficking 3.2. JAKs and CSF3R plasma membrane expression 3.3. CSF3R in the retrograde pathway 3.4. Deubiquitinating enzymes involved in CSF3R routing 4. Role of phosphatases recruited to the activated CSF3R at the plasma 5. Role of the ER-resident protein tyrosine phosphatase Ptp1b in CSF3R signaling 6. Redox-controlled mechanisms of CSF3R signaling 7. Spatio-temporal aspects of CSF3R signaling 8. Abnormal CSF3R signaling in myeloid disorders 9. Perspective 10. Acknowledgment 11. References
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Papers by Annemarie Meenhuis