Mechanistic insights explain the transforming potential of the T507K substitution in the protein-tyrosine phosphatase SHP2
Abstract
The protein-tyrosine phosphatase SHP2 is an allosteric enzyme critical for cellular events downstream of growth factor receptors. Mutations in the SHP2 gene have been linked to many different types of human diseases, including developmental disorders, leukemia, and solid tumors. Unlike most SHP2-activating mutations, the T507K substitution in SHP2 is unique in that it exhibits oncogenic Ras-like transforming activity. However, the biochemical basis of how the SHP2/T507K variant elicits transformation remains unclear. By combining kinetic and biophysical methods, X-ray crystallography, and molecular modeling, as well as using cell biology approaches, in this work we uncovered that the T507K substitution alters both SHP2 substrate specificity and its allosteric regulatory mechanism. We found that although SHP2/T507K exists in the closed, autoinhibited conformation similar to the WT enzyme, the interactions between its N-SH2 and protein-tyrosine phosphatase domains are weakened such that SHP2/T507K possesses a higher affinity for the scaffolding protein Grb2-associated binding protein 1 (Gab1). We also discovered that the T507K substitution alters the structure of the SHP2 active site, resulting in a change in SHP2 substrate preference for Sprouty1, a known negative regulator of Ras signaling and a potential tumor suppressor. Our results suggest that SHP2/T507K's shift in substrate specificity coupled with itsmore »
- Publication Date:
- Research Org.:
- Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
- Sponsoring Org.:
- National Institutes of Health (NIH)
- OSTI Identifier:
- 1630331
- Grant/Contract Number:
- RO1 CA069202; RO1 CA207288
- Resource Type:
- Accepted Manuscript
- Journal Name:
- Journal of Biological Chemistry
- Additional Journal Information:
- Journal Volume: 295; Journal Issue: 18; Journal ID: ISSN 0021-9258
- Publisher:
- American Society for Biochemistry and Molecular Biology
- Country of Publication:
- United States
- Language:
- ENGLISH
- Subject:
- 59 BASIC BIOLOGICAL SCIENCES; 37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY; phosphatase; cancer; transformation; structure–function; kinetics; signaling; mutation; SHP2
Citation Formats
Zhang, Ruo-Yu, Yu, Zhi-Hong, Chen, Lan, Walls, Chad D., Zhang, Sheng, Wu, Li, and Zhang, Zhong-Yin. Mechanistic insights explain the transforming potential of the T507K substitution in the protein-tyrosine phosphatase SHP2. United States: N. p., 2020.
Web. doi:10.1074/jbc.RA119.010274.
Zhang, Ruo-Yu, Yu, Zhi-Hong, Chen, Lan, Walls, Chad D., Zhang, Sheng, Wu, Li, & Zhang, Zhong-Yin. Mechanistic insights explain the transforming potential of the T507K substitution in the protein-tyrosine phosphatase SHP2. United States. https://doi.org/10.1074/jbc.RA119.010274
Zhang, Ruo-Yu, Yu, Zhi-Hong, Chen, Lan, Walls, Chad D., Zhang, Sheng, Wu, Li, and Zhang, Zhong-Yin. Wed .
"Mechanistic insights explain the transforming potential of the T507K substitution in the protein-tyrosine phosphatase SHP2". United States. https://doi.org/10.1074/jbc.RA119.010274. https://www.osti.gov/servlets/purl/1630331.
@article{osti_1630331,
title = {Mechanistic insights explain the transforming potential of the T507K substitution in the protein-tyrosine phosphatase SHP2},
author = {Zhang, Ruo-Yu and Yu, Zhi-Hong and Chen, Lan and Walls, Chad D. and Zhang, Sheng and Wu, Li and Zhang, Zhong-Yin},
abstractNote = {The protein-tyrosine phosphatase SHP2 is an allosteric enzyme critical for cellular events downstream of growth factor receptors. Mutations in the SHP2 gene have been linked to many different types of human diseases, including developmental disorders, leukemia, and solid tumors. Unlike most SHP2-activating mutations, the T507K substitution in SHP2 is unique in that it exhibits oncogenic Ras-like transforming activity. However, the biochemical basis of how the SHP2/T507K variant elicits transformation remains unclear. By combining kinetic and biophysical methods, X-ray crystallography, and molecular modeling, as well as using cell biology approaches, in this work we uncovered that the T507K substitution alters both SHP2 substrate specificity and its allosteric regulatory mechanism. We found that although SHP2/T507K exists in the closed, autoinhibited conformation similar to the WT enzyme, the interactions between its N-SH2 and protein-tyrosine phosphatase domains are weakened such that SHP2/T507K possesses a higher affinity for the scaffolding protein Grb2-associated binding protein 1 (Gab1). We also discovered that the T507K substitution alters the structure of the SHP2 active site, resulting in a change in SHP2 substrate preference for Sprouty1, a known negative regulator of Ras signaling and a potential tumor suppressor. Our results suggest that SHP2/T507K's shift in substrate specificity coupled with its preferential association of SHP2/T507K with Gab1 enable the mutant SHP2 to more efficiently dephosphorylate Sprouty1 at pTyr-53. This dephosphorylation hyperactivates Ras signaling, which is likely responsible for SHP2/T507K's Ras-like transforming activity.},
doi = {10.1074/jbc.RA119.010274},
journal = {Journal of Biological Chemistry},
number = 18,
volume = 295,
place = {United States},
year = {2020},
month = {3}
}
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