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Eriksson, Inger
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Publications (10 of 13) Show all publications
Habicher, J., Haitina, T., Eriksson, I., Holmborn, K., Dierker, T., Ahlberg, P. E. & Ledin, J. (2015). Chondroitin / Dermatan Sulfate Modification Enzymes in Zebrafish Development. PLoS ONE, 10(3), Article ID e0121957.
Open this publication in new window or tab >>Chondroitin / Dermatan Sulfate Modification Enzymes in Zebrafish Development
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2015 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, no 3, article id e0121957Article in journal (Refereed) Published
Abstract [en]

Chondroitin/dermatan sulfate (CS/DS) proteoglycans consist of unbranched sulfated polysaccharide chains of repeating GalNAc-GlcA/IdoA disaccharide units, attached to serine residues on specific proteins. The CS/DS proteoglycans are abundant in the extracellular matrix where they have essential functions in tissue development and homeostasis. In this report a phylogenetic analysis of vertebrate genes coding for the enzymes that modify CS/DS is presented. We identify single orthologous genes in the zebrafish genome for the sulfotransferases chst7, chst11, chst13, chst14, chst15 and ust and the epimerase dse. In contrast, two copies were found for mammalian sulfotransferases CHST3 and CHST12 and the epimerase DSEL, named chst3a and chst3b, chst12a and chst12b, dsela and dselb, respectively. Expression of CS/DS modification enzymes is spatially and temporally regulated with a large variation between different genes. We found that CS/DS 4-O-sulfotransferases and 6-O-sulfotransferases as well as CS/DS epimerases show a strong and partly overlapping expression, whereas the expression is restricted for enzymes with ability to synthesize di-sulfated disaccharides. A structural analysis further showed that CS/DS sulfation increases during embryonic development mainly due to synthesis of 4-O-sulfated GalNAc while the proportion of 6-O-sulfated GalNAc increases in later developmental stages. Di-sulfated GalNAc synthesized by Chst15 and 2-O-sulfated GlcA/IdoA synthesized by Ust are rare, in accordance with the restricted expression of these enzymes. We also compared CS/DS composition with that of heparan sulfate (HS). Notably, CS/DS biosynthesis in early zebrafish development is more dynamic than HS biosynthesis. Furthermore, HS contains disaccharides with more than one sulfate group, which are virtually absent in CS/DS.

National Category
Evolutionary Biology
Identifiers
urn:nbn:se:uu:diva-252231 (URN)10.1371/journal.pone.0121957 (DOI)000352083900161 ()25793894 (PubMedID)
Available from: 2015-05-05 Created: 2015-05-04 Last updated: 2017-12-04Bibliographically approved
Öhrvik, H., Logeman, B., Noguchi, G., Eriksson, I., Kjellen, L., Thiele, D. J. & Pejler, G. (2015). Ctr2 Regulates Mast Cell Maturation by Affecting the Storage and Expression of Tryptase and Proteoglycans. Journal of Immunology, 195(8), 3654-3664
Open this publication in new window or tab >>Ctr2 Regulates Mast Cell Maturation by Affecting the Storage and Expression of Tryptase and Proteoglycans
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2015 (English)In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 195, no 8, p. 3654-3664Article in journal (Refereed) Published
Abstract [en]

Copper (Cu) is essential for multiple cellular functions. Cellular uptake of Cu+ is carried out by the Ctr1 high-affinity Cu transporter. The mobilization of endosomal Cu pools is regulated by a protein structurally similar to Ctr1, called Ctr2. It was recently shown that ablation of Ctr2 caused an increase in the concentration of Cu localized to endolysosomes. However, the biological significance of excess endolysosomal Cu accumulation has not been assessed. In this study, we addressed this issue by investigating the impact of Ctr2 deficiency on mast cells, a cell type unusually rich in endolysosomal organelles (secretory granules). We show that Ctr2(-/-) mast cells have increased intracellular Cu concentrations and that the absence of Ctr2 results in increased metachromatic staining, the latter indicating an impact of Ctr2 on the storage of proteoglycans in the secretory granules. In agreement with this, the absence of Ctr2 caused a skewed ratio between proteoglycans of heparin and chondroitin sulfate type, with increased amounts of heparin accompanied by a reduction of chondroitin sulfate. Moreover, transmission electron microscopy analysis revealed a higher number of electron-dense granules in Ctr2(-/-) mast cells than in wild-type cells. The increase in granular staining and heparin content is compatible with an impact of Ctr2 on mast cell maturation and, in support of this, the absence of Ctr2 resulted in markedly increased mRNA expression, storage, and enzymatic activity of tryptase. Taken together, the present study introduces Ctr2 and Cu as novel actors in the regulation of mast cell maturation and granule homeostasis.

National Category
Immunology in the medical area
Identifiers
urn:nbn:se:uu:diva-266701 (URN)10.4049/jimmunol.1500283 (DOI)000362968100020 ()26342034 (PubMedID)
Funder
Swedish Research Council, 524-2014-1, 521-2013-3870Swedish Cancer SocietySwedish Heart Lung FoundationSwedish Research Council FormasNIH (National Institute of Health), DK074192
Available from: 2015-11-11 Created: 2015-11-10 Last updated: 2018-01-10Bibliographically approved
Pegeot, M., Sadir, R., Eriksson, I., Kjellén, L., Simorre, J.-P., Gans, P. & Lortat-Jacob, H. (2015). Profiling sulfation/epimerization pattern of full-length heparan sulfate by NMR following cell culture C-13-glucose metabolic labeling. Glycobiology, 25(2), 151-156
Open this publication in new window or tab >>Profiling sulfation/epimerization pattern of full-length heparan sulfate by NMR following cell culture C-13-glucose metabolic labeling
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2015 (English)In: Glycobiology, ISSN 0959-6658, E-ISSN 1460-2423, Vol. 25, no 2, p. 151-156Article in journal (Refereed) Published
Abstract [en]

Through its ability to interact with proteins, heparan sulfate (HS) fulfills a large variety of functions. Protein binding depends on the level of HS sulfation and epimerization which are cell specific and dynamically regulated. Characterization of this molecule, however, has been restricted to oligosaccharide fragments available in large amount for structural investigation or to sulfate distribution through compositional analysis. Here we developed a H-1-C-13 2D NMR-based approach, directly performed on HS isolated from C-13-labeled cells. By integrating the peak volumes measured at different chemical shifts, this non-destructive analysis allows us to determine both the sulfation and the iduronic/glucuronic profiles of the polysaccharide. Applied to wild-type and N-deacetylase/N-sulfotransferase-deficient fibroblasts as well as to epithelial cells differentiation, it also gives insights into the functional relationships existing between HS biosynthetic enzymes. This approach should be of significant interest to better understand HS changes that occur through physiologic regulations or during pathological development.

Keywords
C-13-metabolic labeling, heparan sulfate, quantification of GlcA/IdoA epimeriation, sulfation pattern
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:uu:diva-248468 (URN)10.1093/glycob/cwu114 (DOI)000350045000003 ()25335974 (PubMedID)
Available from: 2015-03-30 Created: 2015-03-30 Last updated: 2017-12-04Bibliographically approved
Nguyen, T. K. N., Tran, V. M., Sorna, V., Eriksson, I., Kojima, A., Koketsu, M., . . . Kuberan, B. (2013). Dimerized Glycosaminoglycan Chains Increase FGF Signaling during Zebrafish Development. ACS Chemical Biology, 8(5), 939-948
Open this publication in new window or tab >>Dimerized Glycosaminoglycan Chains Increase FGF Signaling during Zebrafish Development
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2013 (English)In: ACS Chemical Biology, ISSN 1554-8929, E-ISSN 1554-8937, Vol. 8, no 5, p. 939-948Article in journal (Refereed) Published
Abstract [en]

Proteoglycans (PGs) modulate numerous signaling pathways during development through binding of their glycosaminoglycan (GAG) side chains to various signaling molecules, including fibroblast growth factors (FGFs). A majority of PGs possess two or more GAG side chains, suggesting that GAG multivalency is imperative for biological functions in vivo. However, only a few studies have examined the biological significance of GAG multivalency. In this report, we utilized a library of bis- and tris-xylosides that produce two and three GAG chains on the same scaffold, respectively, thus mimicking PGs, to examine the importance of GAG valency and chain type in regulating FGF/FGFR interactions in vivo in zebrafish. A number of bis- and tris-xylosides, but not mono-xylosides, caused an elongation phenotype upon their injection into embryos. In situ hybridization showed that elongated embryos have elevated expression of the FGF target gene mkp3 but unchanged expression of reporters for other pathways, indicating that FGF/FGFR signaling was specifically hyperactivated. In support of this observation, elongation can be reversed by the tyrosine kinase inhibitor SU5402, mRNA for the FGFR antagonist sprouty4, or FGF8 morpholino. Endogenous GAGs seem to be unaffected after xyloside treatment, suggesting that this is a gain-of-function phenotype. Furthermore, expression of a multivalent but not a monovalent GAG containing syndecan-1 proteoglycan recapitulates the elongation phenotype observed with the bivalent xylosides. On the basis of these in vivo findings, we propose a new model for GAG/FGF/FGFR interactions in which dimerized GAG chains can activate FGF-mediated signal transduction pathways.

National Category
Medical and Health Sciences Natural Sciences
Identifiers
urn:nbn:se:uu:diva-203559 (URN)10.1021/cb400132r (DOI)000319720700013 ()
Available from: 2013-07-15 Created: 2013-07-15 Last updated: 2017-12-06Bibliographically approved
Grujic, M., Calounova, G., Eriksson, I., Feyerabend, T., Rodewald, H.-R., Tchougounova, E., . . . Pejler, G. (2013). Distorted Secretory Granule Composition in Mast Cells with Multiple Protease Deficiency. Journal of Immunology, 191(7), 3931-3938
Open this publication in new window or tab >>Distorted Secretory Granule Composition in Mast Cells with Multiple Protease Deficiency
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2013 (English)In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 191, no 7, p. 3931-3938Article in journal (Refereed) Published
Abstract [en]

Mast cells are characterized by an abundance of secretory granules densely packed with inflammatory mediators such as bioactive amines, cytokines, serglycin proteoglycans with negatively charged glycosaminoglycan side chains of either heparin or chondroitin sulfate type, and large amounts of positively charged proteases. Despite the large biological impact of mast cell granules and their contents on various pathologies, the mechanisms that regulate granule composition are incompletely understood. In this study, we hypothesized that granule composition is dependent on a dynamic electrostatic interrelationship between different granule compounds. As a tool to evaluate this possibility, we generated mice in which mast cells are multideficient in a panel of positively charged proteases: the chymase mouse mast cell protease-4, the tryptase mouse mast cell protease-6, and carboxypeptidase A3. Through a posttranslational effect, mast cells from these mice additionally lack mouse mast cell protease-5 protein. Mast cells from mice deficient in individual proteases showed normal morphology. In contrast, mast cells with combined protease deficiency displayed a profound distortion of granule integrity, as seen both by conventional morphological criteria and by transmission electron microscopy. An assessment of granule content revealed that the distorted granule integrity in multiprotease-deficient mast cells was associated with a profound reduction of highly negatively charged heparin, whereas no reduction in chondroitin sulfate storage was observed. Taken together with previous findings showing that the storage of basic proteases conversely is regulated by anionic proteoglycans, these data suggest that secretory granule composition in mast cells is dependent on a dynamic interrelationship between granule compounds of opposite electrical charge.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-209849 (URN)10.4049/jimmunol.1301441 (DOI)000324634500049 ()
Note

G.Calounova and I.Eriksson contributed equally to this work.

Available from: 2013-10-28 Created: 2013-10-28 Last updated: 2017-12-06Bibliographically approved
Filipek-Gorniok, B., Holmborn, K., Haitina, T., Habicher, J., Oliveira, M. B., Hellgren, C., . . . Ledin, J. (2013). Expression of chondroitin/dermatan sulfate glycosyltransferases during early zebrafish development. Developmental Dynamics, 242(8), 964-975
Open this publication in new window or tab >>Expression of chondroitin/dermatan sulfate glycosyltransferases during early zebrafish development
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2013 (English)In: Developmental Dynamics, ISSN 1058-8388, E-ISSN 1097-0177, Vol. 242, no 8, p. 964-975Article in journal (Refereed) Published
Abstract [en]

Background: Chondroitin/dermatan sulfate (CS/DS) proteoglycans present in the extracellular matrix have important structural and regulatory functions. Results: Six human genes have previously been shown to catalyze CS/DS polymerization. Here we show that one of these genes, chpf, is represented by two copies in the zebrafish genome, chpfa and chpfb, while the other five human CS/DS glycosyltransferases csgalnact1, csgalnact2, chpf2, chsy1, and chsy3 all have single zebrafish orthologues. The putative zebrafish CS/DS glycosyltransferases are spatially and temporally expressed. Interestingly, overlapping expression of multiple glycosyltransferases coincides with high CS/DS deposition. Finally, whereas the relative levels of the related polysaccharide HS reach steady-state at around 2 days post fertilization, there is a continued relative increase of the CS amounts per larvae during the first 6 days of development, matching the increased cartilage formation. Conclusions: There are 7 CS/DS glycosyltransferases in zebrafish, which, based on homology, can be divided into the CSGALNACT, CHSY, and CHPF families. The overlap between intense CS/DS production and the expression of multiple CS/DS glycosyltransferases suggests that efficient CS/DS biosynthesis requires a combination of several glycosyltransferases.

Keywords
chondroitin sulfate, polymerase, CSGALNACT, CHSY, CHPF, zebrafish
National Category
Natural Sciences
Identifiers
urn:nbn:se:uu:diva-204834 (URN)10.1002/dvdy.23981 (DOI)000321843400008 ()
Note

De två (2) första författarna delar förstaförfattarskapet.

Available from: 2013-08-13 Created: 2013-08-12 Last updated: 2017-12-06Bibliographically approved
Kasza, Z., Fredlund Fuchs, P., Tamm, C., Eriksson, A. S., O'Callaghan, P., Heindryckx, F., . . . Kreuger, J. (2013). MicroRNA-24 Suppression of N-Deacetylase/N-Sulfotransferase-1 (NDST1) Reduces Endothelial Cell Responsiveness to Vascular Endothelial Growth Factor A (VEGFA). Journal of Biological Chemistry, 288(36), 25956-25963
Open this publication in new window or tab >>MicroRNA-24 Suppression of N-Deacetylase/N-Sulfotransferase-1 (NDST1) Reduces Endothelial Cell Responsiveness to Vascular Endothelial Growth Factor A (VEGFA)
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2013 (English)In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 288, no 36, p. 25956-25963Article in journal (Refereed) Published
Abstract [en]

Heparan sulfate (HS) proteoglycans, present at the plasma membrane of vascular endothelial cells, bind to the angiogenic growth factor VEGFA to modulate its signaling through VEGFR2. The interactions between VEGFA and proteoglycan co-receptors require sulfated domains in the HS chains. To date, it is essentially unknown how the formation of sulfated protein-binding domains in HS can be regulated by microRNAs. In the present study, we show that microRNA-24 (miR-24) targets NDST1 to reduce HS sulfation and thereby the binding affinity of HS for VEGFA. Elevated levels of miR-24 also resulted in reduced levels of VEGFR2 and blunted VEGFA signaling. Similarly, suppression of NDST1 using siRNA led to a reduction in VEGFR2 expression. Consequently, not only VEGFA binding, but also VEGFR2 protein expression is dependent on NDST1 function. Furthermore, overexpression of miR-24, or siRNA-mediated reduction of NDST1, reduced endothelial cell chemotaxis in response to VEGFA. These findings establish NDST1 as a target of miR-24 and demonstrate how such NDST1 suppression in endothelial cells results in reduced responsiveness to VEGFA.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-219873 (URN)10.1074/jbc.M113.484360 (DOI)000330623300026 ()
Available from: 2014-03-12 Created: 2014-03-06 Last updated: 2017-12-05
Le Jan, S., Hayashi, M., Kasza, Z., Eriksson, I., Bishop, J. R., Weibrecht, I., . . . Kreuger, J. (2012). Functional Overlap Between Chondroitin and Heparan Sulfate Proteoglycans During VEGF-Induced Sprouting Angiogenesis. Arteriosclerosis, Thrombosis and Vascular Biology, 32(5), 1255-1263
Open this publication in new window or tab >>Functional Overlap Between Chondroitin and Heparan Sulfate Proteoglycans During VEGF-Induced Sprouting Angiogenesis
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2012 (English)In: Arteriosclerosis, Thrombosis and Vascular Biology, ISSN 1079-5642, E-ISSN 1524-4636, Vol. 32, no 5, p. 1255-1263Article in journal (Refereed) Published
Abstract [en]

OBJECTIVE: Heparan sulfate proteoglycans regulate key steps of blood vessel formation. The present study was undertaken to investigate if there is a functional overlap between heparan sulfate proteoglycans and chondroitin sulfate proteoglycans during sprouting angiogenesis.

METHODS AND RESULTS: Using cultures of genetically engineered mouse embryonic stem cells, we show that angiogenic sprouting occurs also in the absence of heparan sulfate biosynthesis. Cells unable to produce heparan sulfate instead increase their production of chondroitin sulfate that binds key angiogenic growth factors such as vascular endothelial growth factor A, TGFβ, and platelet-derived growth factor B. Lack of heparan sulfate proteoglycan production however leads to increased pericyte numbers and reduced adhesion of pericytes to nascent sprouts, likely due to dysregulation of TGFβ and platelet-derived growth factor B signal transduction.

CONCLUSIONS: The present study provides direct evidence for a previously undefined functional overlap between chondroitin sulfate proteoglycans and heparan sulfate proteoglycans during sprouting angiogenesis. Our findings provide information relevant for potential future drug design efforts that involve targeting of proteoglycans in the vasculature.

Keywords
Angiogenesis, proteoglycan, heparan sulfate, chondroitin sulfate, ext1
National Category
Basic Medicine
Research subject
Medicine; Biology with specialization in Molecular Biology
Identifiers
urn:nbn:se:uu:diva-169136 (URN)10.1161/ATVBAHA.111.240622 (DOI)000303195100031 ()22345168 (PubMedID)
Funder
Swedish Research Council, K2011-67X-21868-01-3
Available from: 2012-02-23 Created: 2012-02-23 Last updated: 2018-01-12Bibliographically approved
Kumaresan, A., Siqueira, A. P., Hossain, M. S., Johannisson, A., Eriksson, I., Wallgren, M. & Bergqvist, A. S. (2012). Quantification of kinetic changes in protein tyrosine phosphorylation and cytosolic Ca2+ concentration in boar spermatozoa during cryopreservation. Reproduction, Fertility and Development, 24(4), 531-542
Open this publication in new window or tab >>Quantification of kinetic changes in protein tyrosine phosphorylation and cytosolic Ca2+ concentration in boar spermatozoa during cryopreservation
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2012 (English)In: Reproduction, Fertility and Development, ISSN 1031-3613, E-ISSN 1448-5990, Vol. 24, no 4, p. 531-542Article in journal (Refereed) Published
Abstract [en]

Protein tyrosine phosphorylation in sperm is associated with capacitation in several mammalian species. Although tyrosine phosphorylated proteins have been demonstrated in cryopreserved sperm, indicating capacitation-like changes during cryopreservation, these changes have not yet been quantified objectively. We monitored tyrosine phosphorylation, intracellular calcium and sperm kinematics throughout the cryopreservation process, and studied the relationships among them in boar spermatozoa. Sperm kinetics changed significantly during cryopreservation: curvilinear velocity, average path velocity and straight line velocity all decreased significantly (P < 0.05). While the percentage of sperm with high intracellular calcium declined (P < 0.05), global phosphorylation increased significantly (P < 0.01). Specifically, cooling to 5 degrees C induced phosphorylation in the spermatozoa. After cooling, a 32-kDa protein not observed in fresh semen appeared and was consistently present throughout the cryopreservation process. While the level of expression of this phosphoprotein decreased after addition of the second extender, frozen-thawed spermatozoa showed an increased expression. The proportion of sperm cells with phosphorylation in the acrosomal area also increased significantly (P < 0.05) during cryopreservation, indicating that phosphorylation might be associated with capacitation-like changes. These results provide the first quantitative evidence of dynamic changes in the subpopulation of boar spermatozoa undergoing tyrosine phosphorylation during cryopreservation.

Keywords
flow cytometry, intracellular calcium, in vitro sperm capacitation
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-174798 (URN)10.1071/RD11074 (DOI)000303123800002 ()
Available from: 2012-05-29 Created: 2012-05-28 Last updated: 2017-12-07Bibliographically approved
Ledin, J., Ringvall, M., Thuveson, M., Eriksson, I., Wilén, M., Kusche-Gullberg, M., . . . Kjellén, L. (2006). Enzymatically active N-deacetylase/N-sulfotransferase-2 is present in liver but does not contribute to heparan sulfate N-sulfation. Journal of Biological Chemistry, 281(47), 35727-35734
Open this publication in new window or tab >>Enzymatically active N-deacetylase/N-sulfotransferase-2 is present in liver but does not contribute to heparan sulfate N-sulfation
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2006 (English)In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 281, no 47, p. 35727-35734Article in journal (Refereed) Published
Abstract [en]

Heparan sulfate (HS) proteoglycans influence embryonic development through interactions with growth factors and morphogens. The interactions depend on HS structure, which is largely determined during biosynthesis by Golgi enzymes. NDST ( glucosaminyl N-deacetylase/N-sulfotransferase), responsible for HSN-sulfation, is a key enzyme directing further modifications including O-sulfation. To elucidate the roles of the different NDST isoforms in HS biosynthesis, we took advantage of mice with targeted mutations in NDST1 and NDST2 and used liver as our model organ. Of the four NDST isoforms, only NDST1 and NDST2 transcripts were shown to be expressed in control liver. The absence of NDST1 or NDST2 in the knock-out mice did not affect transcript levels of other NDST isoforms or other HS modification enzymes. Although the sulfation level of HS synthesized in NDST1(-/-) mice was drastically lowered, liver HS from wild-type mice, from NDST1(-/-), NDST2(-/-), and NDST1(-/-), NDST2(-/-) mice all had the same structure despite greatly reduced NDST enzyme activity (30% of control levels in NDST1(-/-) NDST2(-/-) embryonic day 18.5 embryos). Enzymatically active NDST2 was shown to be present in similar amounts in wild-type, NDST1(-/-), and NDST1(-/-) embryonic day 18.5 liver. Despite the substantial contribution of NDST2 to total NDST enzyme activity in embryonic day 18.5 liver (approximate to 40%), its presence did not appear to affect HS structure as long as NDST1 was also present. In NDST1(-/-) embryonic day 18.5 liver, in contrast, NDST2 was responsible for N-sulfation of the low sulfated HS. A tentative model to explain these results is presented.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-22537 (URN)10.1074/jbc.M604113200 (DOI)000242100500017 ()16984905 (PubMedID)
Available from: 2007-01-18 Created: 2007-01-18 Last updated: 2017-12-07Bibliographically approved
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