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Site-Specific Incorporation of a Phosphotyrosine Mimetic Reveals a Role for Tyrosine Phosphorylation of SHP-2 in Cell Signaling
Open accessAbstract
The regulation of protein tyrosine phosphatase (PTPase) SHP-2 is proposed to involve tyrosine phosphorylation on two tail tyrosine residues. Using "expressed protein ligation", nonhydrolyzable phosphotyrosine analogs were introduced at known phosphorylation sites in SHP-2. Biochemical analysis suggests that a phosphonate at Tyr542 interacts intramolecularly with the N-terminal SH2 domain to relieve basal inhibition of the PTPase, whereas a phosphonate at Tyr-580 stimulates the PTPase activity by interaction with the C-terminal SH2 domain. Microinjection experiments indicate that a single phosphorylation of Tyr-542 of SHP-2 is sufficient to activate the MAP kinase pathway in living cells. These studies support a novel mechanism explaining how tyrosine phosphorylation of a PTPase is important in signal transduction.
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“The lack of influence of SHP2 on robustness of late IL-6-induced STAT3 activation (Fig. 4) might be explained by the fact that SHP2 itself is phosphorylated rapidly in response to IL-6 (Fig. 1b) which causes dissociation from gp130 [9–11].”
From The tyrosine phosphatase SHP2 increases robustness and information transfer within IL-6-induced JAK/STAT signalling (2021) · cites this paper as [9]
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Metadata
- Authors
- Lu, W., Gong, D., Bar-Sagi, D., & Cole, P. A.
- Affiliations
- State University of New York (US)
- Johns Hopkins University (US)
- Corresponding author
- Cole, Philip A
- Venue
- Molecular Cell
- Publisher
- Elsevier BV
- Published
- 2001-10
- Volume
- 8
- Issue
- 4
- Pages
- 759-769
- ISSN
- 1097-2765 (ISSN-L)
- OpenAlex
- W2000348274
- Cited by
- 268
- References
- 57
- Citations by year
- 2026: 7 · 2025: 7 · 2024: 5 · 2023: 8 · 2022: 16 · 2021: 11 · 2020: 13 · 2019: 4 · 2018: 3 · 2017: 11 · 2016: 6 · 2015: 10 · 2014: 8 · 2013: 13 · 2012: 15
- FWCI
- 4.20
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Molecular Cell (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Burroughs Wellcome Fund
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Immunology and Microbiology › Immunology › Cytokine Signaling Pathways and Interactions
- Keywords
- SHP2, tyrosine phosphorylation, phosphotyrosine mimetics, expressed protein ligation, protein tyrosine phosphatase, SH2 domain, MAPK signaling, signal transduction, phosphonate analogs, enzyme activation
- MeSH terms
- Amino Acid Sequence, Enzyme Activation, Microinjections, Microscopy, Fluorescence, Molecular Sequence Data, Phosphorylation, Protein Conformation, Proteins, Recombinant Fusion Proteins, Molecular Structure, Signal Transduction, Culture Media, Serum-Free, Protein Tyrosine Phosphatases, Point Mutation, Phosphotyrosine, Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization, Subtilisin, Intracellular Signaling Peptides and Proteins, Adaptor Proteins, Signal Transducing, GRB2 Adaptor Protein, Protein Tyrosine Phosphatase, Non-Receptor Type 6, Protein Tyrosine Phosphatase, Non-Receptor Type 11, SH2 Domain-Containing Protein Tyrosine Phosphatases
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