Receptor Tyrosine Kinases (RTKs) comprise a diverse group of cell-surface receptors that mediate key signaling events during animal development and are frequently activated in cancer. We show here that deletion of the extracellular regions of 10 RTKs representing 7 RTK classes or their substitution with the dimeric immunoglobulin Fc region results in constitutive receptor phosphorylation but fails to result in phosphorylation of downstream signaling effectors Erk or Akt. Conversely, substitution of RTK extracellular regions with the extracellular region of the Epidermal Growth Factor Receptor (EGFR) results in increases in effector phosphorylation in response to EGF. These results indicate that the activation signal generated by the EGFR extracellular region is capable of activating at least seven different RTK classes. Failure of phosphorylated Fc-RTK chimeras or RTKs with deleted extracellular regions to stimulate phosphorylation of downstream effectors indicates that either dimerization and receptor phosphorylation per se are insufficient to activate signaling or constitutive dimerization leads to pathway inhibition.
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November 2020
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Cover Image
Cover Image
Differential binding of citrate and BI01383298 at the substrate-binding site of human and mouse NaCTs (sodium-coupled citrate transporter). This model provides insight into the molecular basis of selective inhibition of human NaCT by BI01383298. For further information on this model, see the article by Higuchi and colleagues (pp. 4149–4165). Image provided by Vadivel Ganapathy.
Research Article|
November 09 2020
Conserved roles for receptor tyrosine kinase extracellular regions in regulating receptor and pathway activity
Monica Gonzalez-Magaldi;
Monica Gonzalez-Magaldi
Conceptualization, Formal analysis, Investigation, Visualization, Writing - original draft, Writing - review & editing
1Department of Molecular Biosciences, University of Texas at Austin, 100 E. 24th St. Stop A5000, Austin, TX 78712, U.S.A.
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Jacqueline M. McCabe;
Jacqueline M. McCabe
Conceptualization, Formal analysis, Investigation, Writing - review & editing
2Department of Biophysics and Biophysical Chemistry, Johns Hopkins University School of Medicine, 725 N. Wolfe St., Baltimore, MD 21205, U.S.A.
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Haley N. Cartwright;
Haley N. Cartwright
Investigation, Writing - review & editing
1Department of Molecular Biosciences, University of Texas at Austin, 100 E. 24th St. Stop A5000, Austin, TX 78712, U.S.A.
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Ningze Sun;
Ningze Sun
Investigation, Writing - review & editing
1Department of Molecular Biosciences, University of Texas at Austin, 100 E. 24th St. Stop A5000, Austin, TX 78712, U.S.A.
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Daniel J. Leahy
1Department of Molecular Biosciences, University of Texas at Austin, 100 E. 24th St. Stop A5000, Austin, TX 78712, U.S.A.
2Department of Biophysics and Biophysical Chemistry, Johns Hopkins University School of Medicine, 725 N. Wolfe St., Baltimore, MD 21205, U.S.A.
Correspondence: Daniel J. Leahy (dleahy@austin.utexas.edu)
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Publisher: Portland Press Ltd
Received:
September 02 2020
Revision Received:
October 08 2020
Accepted:
October 09 2020
Accepted Manuscript online:
October 12 2020
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© 2020 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society
2020
Biochem J (2020) 477 (21): 4207–4220.
Article history
Received:
September 02 2020
Revision Received:
October 08 2020
Accepted:
October 09 2020
Accepted Manuscript online:
October 12 2020
Citation
Monica Gonzalez-Magaldi, Jacqueline M. McCabe, Haley N. Cartwright, Ningze Sun, Daniel J. Leahy; Conserved roles for receptor tyrosine kinase extracellular regions in regulating receptor and pathway activity. Biochem J 13 November 2020; 477 (21): 4207–4220. doi: https://doi.org/10.1042/BCJ20200702
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