4.6 Article

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

期刊

JOURNAL OF BIOLOGICAL CHEMISTRY
卷 297, 期 1, 页码 -

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AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1016/j.jbc.2021.100883

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  1. American Heart Association
  2. National Institutes of Healthgrants [MH115939, NS105640, NS112121, CA12197]

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Abl family kinases are nonreceptor tyrosine kinases that are activated by phosphorylation upon interaction with PDGFR beta. Specific tyrosine residues play a crucial role in this phosphorylation process, leading to enhanced kinase activity and activation of Abl family kinases.
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 (PDGFR beta), important for cell proliferation and chemotaxis, is a potent activator of Abl family kinases. However, the molecular mechanism by which PDGFR beta 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 PDGFR beta cytoplasmic domain. PDGFR beta 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 PDGFR beta-mediated phosphorylation of Abl2 in vitro activates Abl2 kinase activity, but mutation of these four tyrosines (Y116, Y161, Y272, and Y310) to phenylalanine abrogated PDGFR beta-mediated activation of Abl2. These findings reveal how PDGFR beta 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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