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- W3127828980 abstract "ABSTRACT Eph receptor tyrosine kinases play a key role in cell-cell communication. However, lack of structural information on the entire multi-domain intracellular region of any Eph receptor has hindered detailed understanding of their signaling mechanisms. Here, we use an integrative structural biology approach combining X-ray crystallography, small-angle X-ray scattering and hydrogen-deuterium exchange mass spectrometry, to gain the first insights into the structure and dynamics of the entire EphA2 intracellular region. EphA2 promotes cancer malignancy through a poorly understood non-canonical form of signaling that depends on serine/threonine phosphorylation of the linker connecting the EphA2 kinase and SAM domains. We uncovered two distinct molecular mechanisms that may function in concert to mediate the effects of linker phosphorylation through an orchestrated allosteric regulatory network. The first involves a shift in the equilibrium between a “closed” configuration of the EphA2 intracellular region and an “open” more extended configuration induced by the accumulation of phosphorylation sites in the linker. This implies that cooperation of multiple serine/threonine kinase signaling networks is necessary to promote robust EphA2 non-canonical signaling. The second involves allosteric rearrangements in the kinase domain and juxtamembrane segment induced by phosphorylation of some linker residues, suggesting a link between EphA2 non-canonical signaling and canonical signaling through tyrosine phosphorylation. Given the key role of EphA2 in cancer malignancy, this new knowledge can inform therapeutic strategies." @default.
- W3127828980 created "2021-02-15" @default.
- W3127828980 creator A5000748364 @default.
- W3127828980 creator A5022796313 @default.
- W3127828980 creator A5027148995 @default.
- W3127828980 creator A5043862909 @default.
- W3127828980 creator A5072282453 @default.
- W3127828980 creator A5080215514 @default.
- W3127828980 date "2021-01-29" @default.
- W3127828980 modified "2023-10-15" @default.
- W3127828980 title "Allosteric Regulation of the EphA2 Receptor Intracellular Region by Serine/Threonine Kinases" @default.
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