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The intracellular domains of the EphB6 and EphA10 receptor tyrosine pseudokinases function as dynamic signalling hubs

EphB6 and EphA10 are two poorly characterised pseudokinase members of the Eph receptor family, which collectively serves as mediators of contact-dependent cell–cell communication to transmit extracellular cues into intracellular signals. As per their active counterparts, EphB6 and EphA10 deregulatio...

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Autores principales: Liang, Lung-Yu, Roy, Michael, Horne, Christopher R., Sandow, Jarrod J., Surudoi, Minglyanna, Dagley, Laura F., Young, Samuel N., Dite, Toby, Babon, Jeffrey J., Janes, Peter W., Patel, Onisha, Murphy, James M., Lucet, Isabelle S.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Portland Press Ltd. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8454701/
https://www.ncbi.nlm.nih.gov/pubmed/34431498
http://dx.doi.org/10.1042/BCJ20210572
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author Liang, Lung-Yu
Roy, Michael
Horne, Christopher R.
Sandow, Jarrod J.
Surudoi, Minglyanna
Dagley, Laura F.
Young, Samuel N.
Dite, Toby
Babon, Jeffrey J.
Janes, Peter W.
Patel, Onisha
Murphy, James M.
Lucet, Isabelle S.
author_facet Liang, Lung-Yu
Roy, Michael
Horne, Christopher R.
Sandow, Jarrod J.
Surudoi, Minglyanna
Dagley, Laura F.
Young, Samuel N.
Dite, Toby
Babon, Jeffrey J.
Janes, Peter W.
Patel, Onisha
Murphy, James M.
Lucet, Isabelle S.
author_sort Liang, Lung-Yu
collection PubMed
description EphB6 and EphA10 are two poorly characterised pseudokinase members of the Eph receptor family, which collectively serves as mediators of contact-dependent cell–cell communication to transmit extracellular cues into intracellular signals. As per their active counterparts, EphB6 and EphA10 deregulation is strongly linked to proliferative diseases. However, unlike active Eph receptors, whose catalytic activities are thought to initiate an intracellular signalling cascade, EphB6 and EphA10 are classified as catalytically dead, raising the question of how non-catalytic functions contribute to Eph receptor signalling homeostasis. In this study, we have characterised the biochemical properties and topology of the EphB6 and EphA10 intracellular regions comprising the juxtamembrane (JM) region, pseudokinase and SAM domains. Using small-angle X-ray scattering and cross-linking-mass spectrometry, we observed high flexibility within their intracellular regions in solution and a propensity for interaction between the component domains. We identified tyrosine residues in the JM region of EphB6 as EphB4 substrates, which can bind the SH2 domains of signalling effectors, including Abl, Src and Vav3, consistent with cellular roles in recruiting these proteins for downstream signalling. Furthermore, our finding that EphB6 and EphA10 can bind ATP and ATP-competitive small molecules raises the prospect that these pseudokinase domains could be pharmacologically targeted to counter oncogenic signalling.
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spelling pubmed-84547012021-10-06 The intracellular domains of the EphB6 and EphA10 receptor tyrosine pseudokinases function as dynamic signalling hubs Liang, Lung-Yu Roy, Michael Horne, Christopher R. Sandow, Jarrod J. Surudoi, Minglyanna Dagley, Laura F. Young, Samuel N. Dite, Toby Babon, Jeffrey J. Janes, Peter W. Patel, Onisha Murphy, James M. Lucet, Isabelle S. Biochem J Biochemical Techniques & Resources EphB6 and EphA10 are two poorly characterised pseudokinase members of the Eph receptor family, which collectively serves as mediators of contact-dependent cell–cell communication to transmit extracellular cues into intracellular signals. As per their active counterparts, EphB6 and EphA10 deregulation is strongly linked to proliferative diseases. However, unlike active Eph receptors, whose catalytic activities are thought to initiate an intracellular signalling cascade, EphB6 and EphA10 are classified as catalytically dead, raising the question of how non-catalytic functions contribute to Eph receptor signalling homeostasis. In this study, we have characterised the biochemical properties and topology of the EphB6 and EphA10 intracellular regions comprising the juxtamembrane (JM) region, pseudokinase and SAM domains. Using small-angle X-ray scattering and cross-linking-mass spectrometry, we observed high flexibility within their intracellular regions in solution and a propensity for interaction between the component domains. We identified tyrosine residues in the JM region of EphB6 as EphB4 substrates, which can bind the SH2 domains of signalling effectors, including Abl, Src and Vav3, consistent with cellular roles in recruiting these proteins for downstream signalling. Furthermore, our finding that EphB6 and EphA10 can bind ATP and ATP-competitive small molecules raises the prospect that these pseudokinase domains could be pharmacologically targeted to counter oncogenic signalling. Portland Press Ltd. 2021-09-17 2021-09-14 /pmc/articles/PMC8454701/ /pubmed/34431498 http://dx.doi.org/10.1042/BCJ20210572 Text en © 2021 The Author(s) https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article published by Portland Press Limited on behalf of the Biochemical Society and distributed under the Creative Commons Attribution License 4.0 (CC BY-NC-ND) (https://creativecommons.org/licenses/by-nc-nd/4.0/) .
spellingShingle Biochemical Techniques & Resources
Liang, Lung-Yu
Roy, Michael
Horne, Christopher R.
Sandow, Jarrod J.
Surudoi, Minglyanna
Dagley, Laura F.
Young, Samuel N.
Dite, Toby
Babon, Jeffrey J.
Janes, Peter W.
Patel, Onisha
Murphy, James M.
Lucet, Isabelle S.
The intracellular domains of the EphB6 and EphA10 receptor tyrosine pseudokinases function as dynamic signalling hubs
title The intracellular domains of the EphB6 and EphA10 receptor tyrosine pseudokinases function as dynamic signalling hubs
title_full The intracellular domains of the EphB6 and EphA10 receptor tyrosine pseudokinases function as dynamic signalling hubs
title_fullStr The intracellular domains of the EphB6 and EphA10 receptor tyrosine pseudokinases function as dynamic signalling hubs
title_full_unstemmed The intracellular domains of the EphB6 and EphA10 receptor tyrosine pseudokinases function as dynamic signalling hubs
title_short The intracellular domains of the EphB6 and EphA10 receptor tyrosine pseudokinases function as dynamic signalling hubs
title_sort intracellular domains of the ephb6 and epha10 receptor tyrosine pseudokinases function as dynamic signalling hubs
topic Biochemical Techniques & Resources
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8454701/
https://www.ncbi.nlm.nih.gov/pubmed/34431498
http://dx.doi.org/10.1042/BCJ20210572
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