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PDBsum entry 4jeg
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Signaling protein/protein binding
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PDB id
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4jeg
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References listed in PDB file
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Key reference
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Title
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Dissection of the bcr-Abl signaling network using highly specific monobody inhibitors to the shp2 sh2 domains.
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Authors
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F.Sha,
E.B.Gencer,
S.Georgeon,
A.Koide,
N.Yasui,
S.Koide,
O.Hantschel.
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Ref.
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Proc Natl Acad Sci U S A, 2013,
110,
14924-14929.
[DOI no: ]
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PubMed id
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Abstract
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The dysregulated tyrosine kinase BCR-ABL causes chronic myelogenous leukemia in
humans and forms a large multiprotein complex that includes the Src-homology 2
(SH2) domain-containing phosphatase 2 (SHP2). The expression of SHP2 is
necessary for BCR-ABL-dependent oncogenic transformation, but the precise
signaling mechanisms of SHP2 are not well understood. We have developed binding
proteins, termed monobodies, for the N- and C-terminal SH2 domains of SHP2.
Intracellular expression followed by interactome analysis showed that the
monobodies are essentially monospecific to SHP2. Two crystal structures revealed
that the monobodies occupy the phosphopeptide-binding sites of the SH2 domains
and thus can serve as competitors of SH2-phosphotyrosine interactions.
Surprisingly, the segments of both monobodies that bind to the peptide-binding
grooves run in the opposite direction to that of canonical phosphotyrosine
peptides, which may contribute to their exquisite specificity. When expressed in
cells, monobodies targeting the N-SH2 domain disrupted the interaction of SHP2
with its upstream activator, the Grb2-associated binder 2 adaptor protein,
suggesting decoupling of SHP2 from the BCR-ABL protein complex. Inhibition of
either N-SH2 or C-SH2 was sufficient to inhibit two tyrosine phosphorylation
events that are critical for SHP2 catalytic activity and to block ERK
activation. In contrast, targeting the N-SH2 or C-SH2 revealed distinct roles of
the two SH2 domains in downstream signaling, such as the phosphorylation of
paxillin and signal transducer and activator of transcription 5. Our results
delineate a hierarchy of function for the SH2 domains of SHP2 and validate
monobodies as potent and specific antagonists of protein-protein interactions in
cancer cells.
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