Chemical Dissection of the Effects of Tyrosine Phosphorylation of SHP-2
Abstract
The regulation of the protein tyrosine phosphatase (PTPase) SHP-2 by tyrosine phosphorylation has been difficult to elucidate because of the intrinsic instability of the phosphoprotein. In the past, expressed protein ligation has been used to site-specifically incorporate the phosphotyrosine mimic Pmp (phosphonomethylene phenylalanine) into the two tyrosine phosphorylation sites (542, 580) of SHP-2 one at a time to analyze the effects on catalytic behavior. In this study, we have incorporated two Pmps into the phosphorylation sites simultaneously and examined the effects of double SHP-2 tyrosine phosphorylation. We have found that the Pmp groups show close to additive effects on PTPase stimulation, suggesting dual SH2 domain occupancy. The relative effects of the phosphotyrosine analogue difluoromethylene phosphonophenylalanine (F(2)Pmp) compared to those of Pmp were also examined. It was found that the F(2)Pmp analogue showed slightly enhanced PTPase stimulation compared with the Pmp analogue, consistent with its higher affinity for SH2 domains. Taken together with the bis-Pmp studies, these data suggest that double phosphorylation of the SHP-2 C-terminus could give rise to a 9-fold overall PTPase activation, 30-50% of the value associated with deletion of the SH2 domains. Catalytically inactive forms of phosphorylated SHP-2 proteins were also produced by expressed protein ligation. This allowed for a systematic analysis of intermolecular autodephosphorylation of SHP-2, whic…
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The lack of influence of SHP2 on robustness of late IL-6-induced STAT3 activation might be explained by the fact that SHP2 itself is phosphorylated rapidly in response to IL-6, which causes dissociation from gp130.
“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 [10]
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References 6 · Cited by 59
- Authors
- Lu, W., Shen, K., & Cole, P. A.
- Affiliations
- Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, 725 N. Wolfe Street, Baltimore, Maryland 21205
- Johns Hopkins University (US)
- ORCID
- Cole, Philip A.
- Venue
- Biochemistry
- Publisher
- American Chemical Society (ACS)
- Published
- 2003-04-18
- Volume
- 42
- Issue
- 18
- Pages
- 5461-5468
- ISSN
- 0006-2960 (ISSN-L)
- 1520-4995
- OpenAlex
- W1964992875
- Cited by
- 59
- References
- 6
- Citations by year
- 2026: 2 · 2024: 1 · 2023: 1 · 2022: 3 · 2021: 2 · 2020: 2 · 2019: 2 · 2018: 2 · 2017: 3 · 2016: 3 · 2015: 5 · 2014: 2 · 2013: 2 · 2012: 4
- FWCI
- 1.38
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Biochemistry (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Cancer Institute (R01CA074305)
- 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
- Physical Sciences › Chemistry › Organic Chemistry › Chemical Reaction Mechanisms
- Keywords
- SHP2, tyrosine phosphorylation, protein tyrosine phosphatase, expressed protein ligation, conformational plasticity, SH2 domain
- MeSH terms
- Amino Acid Sequence, Humans, Molecular Sequence Data, Peptide Fragments, Phosphorylation, Protein Binding, Protein Conformation, Recombinant Fusion Proteins, Tyrosine, Signal Transduction, Mutagenesis, Site-Directed, Protein Tyrosine Phosphatases, Point Mutation, Sequence Homology, Amino Acid, src Homology Domains, Phosphotyrosine, Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization, Intracellular Signaling Peptides and Proteins, Protein Tyrosine Phosphatase, Non-Receptor Type 11, SH2 Domain-Containing Protein Tyrosine Phosphatases, Organophosphonates
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