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Platelet-derived growth factor receptor beta activates Abl2 via direct binding and phosphorylation

Abl family kinases are nonreceptor tyrosine kinases activated by diverse cellular stimuli that regulate cytoskeleton organization, morphogenesis, and adhesion. The catalytic activity of Abl family kinases is tightly regulated in cells by a complex set of intramolecular and intermolecular interaction...

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Autores principales: Wu, Kuanlin, Wu, Hanzhi, Lyu, Wanqing, Kim, Youngjoo, Furdui, Cristina M., Anderson, Karen S., Koleske, Anthony J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society for Biochemistry and Molecular Biology 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8259415/
https://www.ncbi.nlm.nih.gov/pubmed/34144039
http://dx.doi.org/10.1016/j.jbc.2021.100883
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author Wu, Kuanlin
Wu, Hanzhi
Lyu, Wanqing
Kim, Youngjoo
Furdui, Cristina M.
Anderson, Karen S.
Koleske, Anthony J.
author_facet Wu, Kuanlin
Wu, Hanzhi
Lyu, Wanqing
Kim, Youngjoo
Furdui, Cristina M.
Anderson, Karen S.
Koleske, Anthony J.
author_sort Wu, Kuanlin
collection PubMed
description Abl family kinases are nonreceptor tyrosine kinases activated by diverse cellular stimuli that regulate cytoskeleton organization, morphogenesis, and adhesion. The catalytic activity of Abl family kinases is tightly regulated in cells by a complex set of intramolecular and intermolecular interactions and post-translational modifications. For example, the platelet-derived growth factor receptor beta (PDGFRβ), important for cell proliferation and chemotaxis, is a potent activator of Abl family kinases. However, the molecular mechanism by which PDGFRβ engages and activates Abl family kinases is not known. We show here that the Abl2 Src homology 2 domain directly binds to phosphotyrosine Y771 in the PDGFRβ cytoplasmic domain. PDGFRβ directly phosphorylates multiple novel sites on the N-terminal half of Abl2, including Y116, Y139, and Y161 within the Src homology 3 domain, and Y299, Y303, and Y310 on the kinase domain. Y116, Y161, Y272, and Y310 are all located at or near the Src homology 3/Src homology 2-kinase linker interface, which helps maintain Abl family kinases in an autoinhibited conformation. We also found that PDGFRβ-mediated phosphorylation of Abl2 in vitro activates Abl2 kinase activity, but mutation of these four tyrosines (Y116, Y161, Y272, and Y310) to phenylalanine abrogated PDGFRβ-mediated activation of Abl2. These findings reveal how PDGFRβ engages and phosphorylates Abl2 leading to activation of the kinase, providing a framework to understand how growth factor receptors engage and activate Abl family kinases.
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spelling pubmed-82594152021-07-12 Platelet-derived growth factor receptor beta activates Abl2 via direct binding and phosphorylation Wu, Kuanlin Wu, Hanzhi Lyu, Wanqing Kim, Youngjoo Furdui, Cristina M. Anderson, Karen S. Koleske, Anthony J. J Biol Chem Research Article Abl family kinases are nonreceptor tyrosine kinases activated by diverse cellular stimuli that regulate cytoskeleton organization, morphogenesis, and adhesion. The catalytic activity of Abl family kinases is tightly regulated in cells by a complex set of intramolecular and intermolecular interactions and post-translational modifications. For example, the platelet-derived growth factor receptor beta (PDGFRβ), important for cell proliferation and chemotaxis, is a potent activator of Abl family kinases. However, the molecular mechanism by which PDGFRβ engages and activates Abl family kinases is not known. We show here that the Abl2 Src homology 2 domain directly binds to phosphotyrosine Y771 in the PDGFRβ cytoplasmic domain. PDGFRβ directly phosphorylates multiple novel sites on the N-terminal half of Abl2, including Y116, Y139, and Y161 within the Src homology 3 domain, and Y299, Y303, and Y310 on the kinase domain. Y116, Y161, Y272, and Y310 are all located at or near the Src homology 3/Src homology 2-kinase linker interface, which helps maintain Abl family kinases in an autoinhibited conformation. We also found that PDGFRβ-mediated phosphorylation of Abl2 in vitro activates Abl2 kinase activity, but mutation of these four tyrosines (Y116, Y161, Y272, and Y310) to phenylalanine abrogated PDGFRβ-mediated activation of Abl2. These findings reveal how PDGFRβ engages and phosphorylates Abl2 leading to activation of the kinase, providing a framework to understand how growth factor receptors engage and activate Abl family kinases. American Society for Biochemistry and Molecular Biology 2021-06-16 /pmc/articles/PMC8259415/ /pubmed/34144039 http://dx.doi.org/10.1016/j.jbc.2021.100883 Text en © 2021 The Authors https://creativecommons.org/licenses/by/4.0/This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Research Article
Wu, Kuanlin
Wu, Hanzhi
Lyu, Wanqing
Kim, Youngjoo
Furdui, Cristina M.
Anderson, Karen S.
Koleske, Anthony J.
Platelet-derived growth factor receptor beta activates Abl2 via direct binding and phosphorylation
title Platelet-derived growth factor receptor beta activates Abl2 via direct binding and phosphorylation
title_full Platelet-derived growth factor receptor beta activates Abl2 via direct binding and phosphorylation
title_fullStr Platelet-derived growth factor receptor beta activates Abl2 via direct binding and phosphorylation
title_full_unstemmed Platelet-derived growth factor receptor beta activates Abl2 via direct binding and phosphorylation
title_short Platelet-derived growth factor receptor beta activates Abl2 via direct binding and phosphorylation
title_sort platelet-derived growth factor receptor beta activates abl2 via direct binding and phosphorylation
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8259415/
https://www.ncbi.nlm.nih.gov/pubmed/34144039
http://dx.doi.org/10.1016/j.jbc.2021.100883
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