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PDBsum entry 5czi
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References listed in PDB file
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Key reference
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Title
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Egf-Receptor specificity for phosphotyrosine-Primed substrates provides signal integration with src.
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Authors
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M.J.Begley,
C.H.Yun,
C.A.Gewinner,
J.M.Asara,
J.L.Johnson,
A.J.Coyle,
M.J.Eck,
I.Apostolou,
L.C.Cantley.
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Ref.
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Nat Struct Biol, 2015,
22,
983-990.
[DOI no: ]
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PubMed id
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Abstract
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Aberrant activation of the EGF receptor (EGFR) contributes to many human cancers
by activating the Ras-MAPK pathway and other pathways. EGFR signaling is
augmented by Src-family kinases, but the mechanism is poorly understood. Here,
we show that human EGFR preferentially phosphorylates peptide substrates that
are primed by a prior phosphorylation. Using peptides based on the sequence of
the adaptor protein Shc1, we show that Src mediates the priming phosphorylation,
thus promoting subsequent phosphorylation by EGFR. Importantly, the doubly
phosphorylated Shc1 peptide binds more tightly than singly phosphorylated
peptide to the Ras activator Grb2; this binding is a key step in activating the
Ras-MAPK pathway. Finally, a crystal structure of EGFR in complex with a primed
Shc1 peptide reveals the structural basis for EGFR substrate specificity. These
results provide a molecular explanation for the integration of Src and EGFR
signaling with downstream effectors such as Ras.
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