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Tetraspanin CD82 Regulates the Spatiotemporal Dynamics of PKCα in Acute Myeloid Leukemia

Patients with acute myeloid leukemia (AML) have increased myeloid cells within their bone marrow that exhibit aberrant signaling. Therefore, therapeutic targets that modulate disrupted signaling cascades are of significant interest. In this study, we demonstrate that the tetraspanin membrane scaffol...

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Autores principales: Termini, Christina M., Lidke, Keith A., Gillette, Jennifer M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4945921/
https://www.ncbi.nlm.nih.gov/pubmed/27417454
http://dx.doi.org/10.1038/srep29859
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author Termini, Christina M.
Lidke, Keith A.
Gillette, Jennifer M.
author_facet Termini, Christina M.
Lidke, Keith A.
Gillette, Jennifer M.
author_sort Termini, Christina M.
collection PubMed
description Patients with acute myeloid leukemia (AML) have increased myeloid cells within their bone marrow that exhibit aberrant signaling. Therefore, therapeutic targets that modulate disrupted signaling cascades are of significant interest. In this study, we demonstrate that the tetraspanin membrane scaffold, CD82, regulates protein kinase c alpha (PKCα)-mediated signaling critical for AML progression. Utilizing a palmitoylation mutant form of CD82 with disrupted membrane organization, we find that the CD82 scaffold controls PKCα expression and activation. Combining single molecule and ensemble imaging measurements, we determine that CD82 stabilizes PKCα activation at the membrane and regulates the size of PKCα membrane clusters. Further evaluation of downstream effector signaling identified robust and sustained activation of ERK1/2 upon CD82 overexpression that results in enhanced AML colony formation. Together, these data propose a mechanism where CD82 membrane organization regulates sustained PKCα signaling that results in an aggressive leukemia phenotype. These observations suggest that the CD82 scaffold may be a potential therapeutic target for attenuating aberrant signal transduction in AML.
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spelling pubmed-49459212016-07-26 Tetraspanin CD82 Regulates the Spatiotemporal Dynamics of PKCα in Acute Myeloid Leukemia Termini, Christina M. Lidke, Keith A. Gillette, Jennifer M. Sci Rep Article Patients with acute myeloid leukemia (AML) have increased myeloid cells within their bone marrow that exhibit aberrant signaling. Therefore, therapeutic targets that modulate disrupted signaling cascades are of significant interest. In this study, we demonstrate that the tetraspanin membrane scaffold, CD82, regulates protein kinase c alpha (PKCα)-mediated signaling critical for AML progression. Utilizing a palmitoylation mutant form of CD82 with disrupted membrane organization, we find that the CD82 scaffold controls PKCα expression and activation. Combining single molecule and ensemble imaging measurements, we determine that CD82 stabilizes PKCα activation at the membrane and regulates the size of PKCα membrane clusters. Further evaluation of downstream effector signaling identified robust and sustained activation of ERK1/2 upon CD82 overexpression that results in enhanced AML colony formation. Together, these data propose a mechanism where CD82 membrane organization regulates sustained PKCα signaling that results in an aggressive leukemia phenotype. These observations suggest that the CD82 scaffold may be a potential therapeutic target for attenuating aberrant signal transduction in AML. Nature Publishing Group 2016-07-15 /pmc/articles/PMC4945921/ /pubmed/27417454 http://dx.doi.org/10.1038/srep29859 Text en Copyright © 2016, Macmillan Publishers Limited http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
spellingShingle Article
Termini, Christina M.
Lidke, Keith A.
Gillette, Jennifer M.
Tetraspanin CD82 Regulates the Spatiotemporal Dynamics of PKCα in Acute Myeloid Leukemia
title Tetraspanin CD82 Regulates the Spatiotemporal Dynamics of PKCα in Acute Myeloid Leukemia
title_full Tetraspanin CD82 Regulates the Spatiotemporal Dynamics of PKCα in Acute Myeloid Leukemia
title_fullStr Tetraspanin CD82 Regulates the Spatiotemporal Dynamics of PKCα in Acute Myeloid Leukemia
title_full_unstemmed Tetraspanin CD82 Regulates the Spatiotemporal Dynamics of PKCα in Acute Myeloid Leukemia
title_short Tetraspanin CD82 Regulates the Spatiotemporal Dynamics of PKCα in Acute Myeloid Leukemia
title_sort tetraspanin cd82 regulates the spatiotemporal dynamics of pkcα in acute myeloid leukemia
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4945921/
https://www.ncbi.nlm.nih.gov/pubmed/27417454
http://dx.doi.org/10.1038/srep29859
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