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508 results on '"Claesson-Welsh, L."'

2. Claudin5 protects the peripheral endothelial barrier in an organ and vessel-type-specific manner

Author

Richards, M. (Mark), Nwadozi, E. (Emmanuel), Pal, S. (Sagnik), Martinsson, P. (Pernilla), Kaakinen, M. (Mika), Gloger, M. (Marleen), Sjöberg, E. (Elin), Koltowska, K. (Katarzyna), Betsholtz, C. (Christer), Eklund, L. (Lauri), Nordling, S. (Sofia), Claesson-Welsh, L. (Lena), Richards, M. (Mark), Nwadozi, E. (Emmanuel), Pal, S. (Sagnik), Martinsson, P. (Pernilla), Kaakinen, M. (Mika), Gloger, M. (Marleen), Sjöberg, E. (Elin), Koltowska, K. (Katarzyna), Betsholtz, C. (Christer), Eklund, L. (Lauri), Nordling, S. (Sofia), and Claesson-Welsh, L. (Lena)

Abstract

Dysfunctional and leaky blood vessels resulting from disruption of the endothelial cell (EC) barrier accompanies numerous diseases. The EC barrier is established through endothelial cell tight and adherens junctions. However, the expression pattern and precise contribution of different junctional proteins to the EC barrier is poorly understood. Here, we focus on organs with continuous endothelium to identify structural and functional in vivo characteristics of the EC barrier. Assembly of multiple single-cell RNAseq datasets into a single integrated database revealed the variability and commonalities of EC barrier patterning. Across tissues, Claudin5 exhibited diminishing expression along the arteriovenous axis, correlating with EC barrier integrity. Functional analysis identified tissue-specific differences in leakage properties and response to the leakage agonist histamine. Loss of Claudin5 enhanced histamine-induced leakage in an organotypic and vessel type-specific manner in an inducible, EC-specific, knock-out mouse. Mechanistically, Claudin5 loss left junction ultrastructure unaffected but altered its composition, with concomitant loss of zonula occludens-1 and upregulation of VE-Cadherin expression. These findings uncover the organ-specific organisation of the EC barrier and distinct importance of Claudin5 in different vascular beds, providing insights to modify EC barrier stability in a targeted, organ-specific manner.

Published
2022

3. Tyrosine-protein kinase Yes controls endothelial junctional plasticity and barrier integrity by regulating VE-cadherin phosphorylation and endocytosis

Author

Jin, Y. (Yi), Ding, Y. (Yindi), Richards, M. (Mark), Kaakinen, M. (Mika), Giese, W. (Wolfgang), Baumann, E. (Elisabeth), Szymborska, A. (Anna), Rosa, A. (André), Nordling, S. (Sofia), Schimmel, L. (Lilian), Akmeriç, E. B. (Emir Bora), Pena, A. (Andreia), Nwadozi, E. (Emmanuel), Jamalpour, M. (Maria), Holstein, K. (Katrin), Sáinz-Jaspeado, M. (Miguel), Bernabeu, M. O. (Miguel O.), Welsh, M. (Michael), Gordon, E. (Emma), Franco, C. A. (Claudio A.), Vestweber, D. (Dietmar), Eklund, L. (Lauri), Gerhardt, H. (Holger), Claesson-Welsh, L. (Lena), Jin, Y. (Yi), Ding, Y. (Yindi), Richards, M. (Mark), Kaakinen, M. (Mika), Giese, W. (Wolfgang), Baumann, E. (Elisabeth), Szymborska, A. (Anna), Rosa, A. (André), Nordling, S. (Sofia), Schimmel, L. (Lilian), Akmeriç, E. B. (Emir Bora), Pena, A. (Andreia), Nwadozi, E. (Emmanuel), Jamalpour, M. (Maria), Holstein, K. (Katrin), Sáinz-Jaspeado, M. (Miguel), Bernabeu, M. O. (Miguel O.), Welsh, M. (Michael), Gordon, E. (Emma), Franco, C. A. (Claudio A.), Vestweber, D. (Dietmar), Eklund, L. (Lauri), Gerhardt, H. (Holger), and Claesson-Welsh, L. (Lena)

Abstract

Vascular endothelial (VE)-cadherin in endothelial adherens junctions is an essential component of the vascular barrier, critical for tissue homeostasis and implicated in diseases such as cancer and retinopathies. Inhibitors of Src cytoplasmic tyrosine kinase have been applied to suppress VE-cadherin tyrosine phosphorylation and prevent excessive leakage, edema and high interstitial pressure. Here we show that the Src-related Yes tyrosine kinase, rather than Src, is localized at endothelial cell (EC) junctions where it becomes activated in a flow-dependent manner. EC-specific Yes1 deletion suppresses VE-cadherin phosphorylation and arrests VE-cadherin at EC junctions. This is accompanied by loss of EC collective migration and exaggerated agonist-induced macromolecular leakage. Overexpression of Yes1 causes ectopic VE-cadherin phosphorylation, while vascular leakage is unaffected. In contrast, in EC-specific Src deficiency, VE-cadherin internalization is maintained and leakage is suppressed. In conclusion, Yes-mediated phosphorylation regulates constitutive VE-cadherin turnover, thereby maintaining endothelial junction plasticity and vascular integrity.

Published
2022

13. Novel high affinity affibody for radionuclide imaging of VEGFR2 in glioma vasculature : proof-of-principle in murine model

Author

Mitran, B., Güler, Rezan, Roche, F. P., Lindström, E., Selvaraju, R., Fleetwood, Filippa, Rinne, S. S., Claesson-Welsh, L., Tolmachev, V., Ståhl, Stefan, Orlova, A., Löfblom, John, Mitran, B., Güler, Rezan, Roche, F. P., Lindström, E., Selvaraju, R., Fleetwood, Filippa, Rinne, S. S., Claesson-Welsh, L., Tolmachev, V., Ståhl, Stefan, Orlova, A., and Löfblom, John

Abstract

QC 20200310

Published
2017

14. Highly sensitive and specific protein detection via combined capillary isoelectric focusing and proximity ligation

Author

Padhan, N., Yan, J., Boge, A., Scrivener, E., Birgisson, H., Zieba, A., Gullberg, M., Kamali-Moghaddam, M., Claesson-Welsh, L., Landegren, U., Padhan, N., Yan, J., Boge, A., Scrivener, E., Birgisson, H., Zieba, A., Gullberg, M., Kamali-Moghaddam, M., Claesson-Welsh, L., and Landegren, U.

Abstract

Detection and quantification of proteins and their post-translational modifications are crucial to decipher functions of complex protein networks in cell biology and medicine. Capillary isoelectric focusing together with antibody-based detection can resolve and identify proteins and their isoforms with modest sample input. However, insufficient sensitivity prevents detection of proteins present at low concentrations and antibody cross-reactivity results in unspecific detection that cannot be distinguished from bona fide protein isoforms. By using DNA-conjugated antibodies enhanced signals can be obtained via rolling circle amplification (RCA). Both sensitivity and specificity can be greatly improved in assays dependent on target recognition by pairs of antibodies using in situ proximity ligation assays (PLA). Here we applied these DNA-assisted RCA techniques in capillary isoelectric focusing to resolve endogenous signaling transducers and isoforms along vascular endothelial growth factor (VEGF) signaling pathways at concentrations too low to be detected in standard assays. We also demonstrate background rejection and enhanced specificity when protein detection depended on binding by pairs of antibodies using in situ PLA, compared to assays where each antibody preparation was used on its own.

Published
2017

17. p73 is required for endothelial cell differentiation, migration and the formation of vascular networks regulating VEGF and TGFβ signaling

Author

Fernandez-Alonso, R, primary, Martin-Lopez, M, additional, Gonzalez-Cano, L, additional, Garcia, S, additional, Castrillo, F, additional, Diez-Prieto, I, additional, Fernandez-Corona, A, additional, Lorenzo-Marcos, M E, additional, Li, X, additional, Claesson-Welsh, L, additional, Marques, M M, additional, and Marin, M C, additional

Published
2015
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21. Molecular interactions of the Src homology 2 domain protein Shb with phosphotyrosine residues, tyrosine kinase receptors and Src homology 3 domain proteins

Author

Karlsson T, Songyang Z, Landgren E, Lavergne C, Pp, Di Fiore, Anafi M, Pawson T, Lc, Cantley, Claesson-Welsh L, and Welsh M

Subjects
Platelet-Derived Growth Factor, Binding Sites, Base Sequence, Molecular Sequence Data, Receptor Protein-Tyrosine Kinases, Receptors, Fibroblast Growth Factor, Oncogene Protein pp60(v-src), Proto-Oncogene Proteins, Animals, Tyrosine, Receptors, Platelet-Derived Growth Factor, Amino Acid Sequence, Rabbits, Phosphotyrosine
Abstract

The molecular interactions of the Src homology 2 (SH2) domain and the N-terminal proline-rich sequence motifs (pro-1 to pro-5) of the SH2 protein Shb with other components were presently characterised. Using a degenerate phosphopeptide library the preferred binding site for the Shb SH2 domain was determined to pTyr-Thr/Val/Ile-X-Leu at positions +1 to +3 relative the phosphotyrosine residue. Experiments with competing peptides and platelet-derived growth factor (PDGF) beta-receptor mutants with Y to F substitutions in autophosphorylation sites revealed multiple binding sites for the Shb SH2 domain in the receptor. The Shb SH2 domain also binds to in vitro phosphorylated fibroblast growth factor receptor-1 (FGFR-1) mainly through position Y776. The receptor experiments suggest that other residues besides the +1 to +3 positions may also be of significance for Shb binding. The pro-4/pro-5 motif of Shb binds in vitro particularly well to the Src, p85 alpha PI3-kinase and Eps8 SH3 domains expressed as GST fusion proteins. However, the GST-SH3 domain fusion proteins tested bind in vitro to peptides corresponding to the pro-1 to pro-5 motifs of Shb with low affinity and selectivity, suggesting that sequences outside the core proline motif may also be important for Shb-SH3 domain interactions. In vivo association between Shb-SH3 domain proteins v-Src and Eps8 was detected by coimmunoprecipitation. PDGF treatment did not affect the association between Eps8 and Shb. The data suggest that Shb is an adaptor protein linking SH3 domain proteins to tyrosine kinases or other tyrosine phosphorylated proteins.

Published
1995

25. VEGF-receptor signal transduction

Author

Cross, MJ, Dixelius, J, Matsumoto, T, Claesson-Welsh, L, Cross, MJ, Dixelius, J, Matsumoto, T, and Claesson-Welsh, L

Published
2003

29. Shb is a ubiquitously expressed Src homology 2 protein

Author

Welsh M, Mares J, Karlsson T, Lavergne C, Bréant B, and Claesson-Welsh L

Subjects
DNA, Complementary, Base Sequence, Sequence Homology, Amino Acid, Molecular Sequence Data, Protein-Tyrosine Kinases, Cell Line, Genes, src, Islets of Langerhans, Mice, Gene Expression Regulation, Proto-Oncogene Proteins, Animals, Humans, Amino Acid Sequence, Adaptor Proteins, Signal Transducing, Signal Transduction
Abstract

To identify serum-inducible genes in the insulin-producing cell line beta TC-1, a library subtraction screening procedure was performed on serum-deprived (G0) and serum-restimulated (G1) insulin-producing beta TC-1 cells. A cDNA containing a motif with strong homology to Src homology 2 (SH2) domains was found using this procedure and called Shb. The Shb cDNA contains two methionine codons in its N-terminus and thus may code for two proteins of 67 and 56 kDa, each with one SH2 domain in its C-terminus. No other structural similarity to proteins with catalytic activity could be detected, suggesting that Shb is a so called adaptor. Shb contains the proline-rich sequence PPPGPGR between the two proposed initiator methionines which resembles a sequence for binding to Src homology 3 (SH3) domains. A second proline-rich sequence was detected after the second methionine codon. The Shb cDNA hybridized to a similar or identical mRNA of 3.1 kb expressed in mouse brain, liver, kidney, heart, NIH3T3 fibroblasts and beta TC-1 cells. Western blot analysis of the same tissues using an antiserum directed against a synthetic peptide corresponding to a part of the SH2 domain of Shb, revealed reactivity with two proteins of 56 and 67 kDa. In addition, a third reactive component of 40 kDa was detected in most tissues. Transfection and transient expression of the Shb cDNA in COS-1 cells yielded increased expression of the 67, 56 and 40 kDa proteins. Transfection and stable expression of the Shb cDNA in pig aortic endothelial cells showed increased expression primarily of the 67 kDa protein. A fusion protein consisting of the SH2 domain of Shb linked to glutathione S-transferase showed increased binding to glycoproteins of cells stimulated with platelet-derived growth factor (PDGF-BB). Furthermore, the autophosphorylated PDGF beta-receptor but not the autophosphorylated epidermal growth factor (EGF) receptor bound specifically to immobilized fusion protein. It is concluded that Shb is a novel SH2-containing protein with proline-rich domains and therefore probably involved in the signal-transduction of some ligand-activated tyrosine kinase receptors.

Published
1994

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