Structural reorganization of SHP2 by oncogenic mutations and implications for oncoprotein resistance to allosteric inhibition
Open accessAbstract
Activating mutations in PTPN11 , encoding the cytosolic protein tyrosine phosphatase SHP2, result in developmental disorders and act as oncogenic drivers in patients with hematologic cancers. The allosteric inhibitor SHP099 stabilizes the wild-type SHP2 enzyme in an autoinhibited conformation that is itself destabilized by oncogenic mutations. Here, we report the impact of the highly activated and most frequently observed mutation, E76K, on the structure of SHP2, and investigate the effect of E76K and other oncogenic mutations on allosteric inhibition by SHP099. SHP2 E76K adopts an open conformation but can be restored to the closed, autoinhibited conformation, near-identical to the unoccupied wild-type enzyme, when complexed with SHP099. SHP099 inhibitory activity against oncogenic SHP2 variants in vitro and in cells scales inversely with the activating strength of the mutation, indicating that either oncoselective or vastly more potent inhibitors will be necessary to suppress oncogenic signaling by the most strongly activating SHP2 mutations in cancer.
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SHP099 and ET070 correct hyperactivation of mutant SHP2 by stabilizing its closed conformation.
“Simple synthetic compounds can also function as intramolecular glues, as shown by SHP099 110,111 and ET070 (Fig. 6), 112 which correct the hyperactivation of mutant SHP2 by stabilizing its closed conformation.”
From Chasing molecular glue degraders: screening approaches (2022) · cites this paper as [111]
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Cites
Features and development of Coot
Emsley, P., Lohkamp, B., Scott, W. G., & Cowtan, K. D. (2010) · Acta Crystallographica Section D Biological Crystallography · doi:10.1107/s0907444910007493 · Cited by 27,510 · see citing works
<i>Phaser</i> crystallographic software
McCoy, A. J., Grosse-Kunstleve, R. W., Adams, P. D., Winn, M. D., Storoni, L. C., & Read, R. J. (2007) · Journal of Applied Crystallography · doi:10.1107/s0021889807021206 · Cited by 20,612 · see citing works
Kabsch, W. (2010) · Acta Crystallographica Section D Biological Crystallography · doi:10.1107/s0907444909047337 · Cited by 16,463 · see citing works
Genome engineering using the CRISPR-Cas9 system
Ran, F. A., Hsu, P. D., Wright, J., Agarwala, V., Scott, D. A., & Zhang, F. (2013) · Nature Protocols · doi:10.1038/nprot.2013.143 · Cited by 11,133 · see citing works
New developments in the ATSAS program package for small-angle scattering data analysis
Petoukhov, M. V., Franke, D., Shkumatov, A. V., Tria, G., Kikhney, A., Gajda, M. J., Gorba, C., Mertens, H. D. T., Konarev, P. V., & Svergun, D. I. (2012) · Journal of Applied Crystallography · doi:10.1107/s0021889812007662 · Cited by 1,907 · see citing works
Mutations in PTPN11, encoding the protein tyrosine phosphatase SHP-2, cause Noonan syndrome
Tartaglia, M., Mehler, E. L., Goldberg, R. B., Zampino, G., Brunner, H. G., Kremer, H., van der Burgt, I., Crosby, A. H., Ion, A., Jeffery, S., et al. (2001) · Nature Genetics · doi:10.1038/ng772 · Cited by 1,736 · see citing works
Drug-target residence time and its implications for lead optimization
Copeland, R. A., Pompliano, D. L., & Meek, T. D. (2006) · Nature Reviews Drug Discovery · doi:10.1038/nrd2082 · Cited by 1,464 · see citing works
The ‘Shp'ing news: SH2 domain-containing tyrosine phosphatases in cell signaling
Neel, B. G., Gu, H., & Pao, L. (2003) · Trends in Biochemical Sciences · doi:10.1016/s0968-0004(03)00091-4 · Cited by 1,249 · see citing works
Tartaglia, M., Niemeyer, C. M., Fragale, A., Song, X., Buechner, J., Jung, A., Hählen, K., Hasle, H., Licht, J. D., & Gelb, B. D. (2003) · Nature Genetics · doi:10.1038/ng1156 · Cited by 1,033 · see citing works
Crystal Structure of the Tyrosine Phosphatase SHP-2
Hof, P., Pluskey, S., Dhe‐Paganon, S., Eck, M. J., & Shoelson, S. E. (1998) · Cell · doi:10.1016/s0092-8674(00)80938-1 · Cited by 996 · see citing works
Allosteric inhibition of SHP2 phosphatase inhibits cancers driven by receptor tyrosine kinases
Chen, Y.-N. P., LaMarche, M. J., Chan, H. M., Fekkes, P., Garcia-Fortanet, J., Acker, M. G., Antonakos, B., Chen, C. H.-T., Chen, Z., Cooke, V. G., et al. (2016) · Nature · doi:10.1038/nature18621 · Cited by 925 · see citing works
Self-citationSmart, O. S., Womack, T. O., Flensburg, C., Keller, P., Paciorek, W., Sharff, A., Vonrhein, C., & Bricogne, G. (2012) · Acta Crystallographica Section D Biological Crystallography · doi:10.1107/s0907444911056058 · Cited by 612 · see citing works
The tyrosine phosphatase Shp2 (PTPN11) in cancer
Chan, G., Kalaitzidis, D., & Neel, B. G. (2008) · Cancer and Metastasis Reviews · doi:10.1007/s10555-008-9126-y · Cited by 383 · see citing works
Noguchi, T., Matozaki, T., Horita, K., Fujioka, Y., & Kasuga, M. (1994) · Molecular and Cellular Biology · doi:10.1128/mcb.14.10.6674 · Cited by 376 · see citing works
Garcia Fortanet, J., Chen, C. H.-T., Chen, Y.-N. P., Chen, Z., Deng, Z., Firestone, B., Fekkes, P., Fodor, M., Fortin, P. D., Fridrich, C., et al. (2016) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.6b00680 · Cited by 298 · see citing works
Self-citationPotent Stimulation of SH-PTP2 Phosphatase Activity by Simultaneous Occupancy of Both SH2 Domains
Pluskey, S., Wandless, T. J., Walsh, C. T., & Shoelson, S. E. (1995) · Journal of Biological Chemistry · doi:10.1074/jbc.270.7.2897 · Cited by 285 · see citing works
Mohi, G., Williams, I. R., Dearolf, C. R., Chan, G., Kutok, J. L., Cohen, S. L., Morgan, K. J., Boulton, C. L., Shigematsu, H., Keilhack, H., et al. (2005) · Cancer Cell · doi:10.1016/j.ccr.2005.01.010 · Cited by 274 · see citing works
Zhang, J., Zhang, F., & Niu, R. (2015) · Journal of Cellular and Molecular Medicine · doi:10.1111/jcmm.12618 · Cited by 253 · see citing works
Li, J., Jie, H.-B., Lei, Y. L., Gildener‐Leapman, N., Trivedi, S., Green, T., Kane, L., & Ferris, R. L. (2014) · Cancer Research · doi:10.1158/0008-5472.can-14-1215 · Cited by 252 · see citing works
WGE: a CRISPR database for genome engineering
Hodgkins, A., Farne, A., Perera, S., Grego, T., Parry-Smith, D., Skarnes, W., & Iyer, V. (2015) · Bioinform. · doi:10.1093/bioinformatics/btv308 · Cited by 202 · see citing works
Drugging the Undruggable: Therapeutic Potential of Targeting Protein Tyrosine Phosphatases
Zhang, Z. (2016) · Accounts of Chemical Research · doi:10.1021/acs.accounts.6b00537 · Cited by 191 · see citing works
PTPN11 is a central node in intrinsic and acquired resistance to targeted cancer drugs
Prahallad, A., Heynen, G. J. J. E., Germano, G., Willems, S. M., Evers, B., Vecchione, L., Gambino, V., Lieftink, C., Beijersbergen, R. L., Di Nicolantonio, F., et al. (2015) · Cell Reports · doi:10.1016/j.celrep.2015.08.037 · Cited by 168 · see citing works
Therapeutic Potential of Targeting the Oncogenic SHP2 Phosphatase
Zeng, L., Zhang, R., Yu, Z.-H., Li, S., Wu, L., Gunawan, A. M., Lane, B. S., Mali, R. S., Li, X., Chan, R. J., et al. (2014) · Journal of Medicinal Chemistry · doi:10.1021/jm5006176 · Cited by 139 · see citing works
Liquid-chromatography-coupled SAXS for accurate sizing of aggregating proteins
Mathew, E., Mirza, A. A., & Menhart, N. (2004) · Journal of Synchrotron Radiation · doi:10.1107/s0909049504014086 · Cited by 133 · see citing works
Dual Allosteric Inhibition of SHP2 Phosphatase
Fodor, M., Price, E. V., Wang, P., Lu, H., Argintaru, A., Chen, Z., Glick, M., Hao, H.-X., Kato, M., Koenig, R., et al. (2018) · ACS Chemical Biology · doi:10.1021/acschembio.7b00980 · Cited by 133 · see citing works
Self-citationNoguchi, T., Matozaki, T., Horita, K., et al. (1994) · Molecular and Cellular Biology · doi:10.1128/mcb.14.10.6674-6682.1994 · Cited by 114 · see citing works
Crystal structure of human protein tyrosine phosphatase SHP-1 in the open conformation
Wang, W., Liu, L., Song, X., Mo, Y., Komma, C., Bellamy, H. D., Zhao, Z. J., & Zhou, G. W. (2011) · Journal of Cellular Biochemistry · doi:10.1002/jcb.23125 · Cited by 102 · see citing works
LaRochelle, J. R., Fodor, M., Xu, X., Durzynska, I., Fan, L., Stams, T., Chan, H. M., LaMarche, M. J., Chopra, R., Wang, P., et al. (2016) · Biochemistry · doi:10.1021/acs.biochem.5b01287 · Cited by 70 · see citing works
Self-citationSHP2 phosphatase as a novel therapeutic target for melanoma treatment
Zhang, R., Yu, Z.-H., Zeng, L., Zhang, S., Bai, Y., Miao, J., Chen, L., Xie, J., & Zhang, Z. (2016) · Oncotarget · doi:10.18632/oncotarget.12074 · Cited by 55 · see citing works
Off‐target inhibition by active site‐targeting <scp>SHP</scp> 2 inhibitors
Tsutsumi, R., Ran, H., & Neel, B. G. (2018) · FEBS Open Bio · doi:10.1002/2211-5463.12493 · Cited by 54 · see citing works
LaRochelle, J. R., Fodor, M., Ellegast, J. M., Liu, X., Vemulapalli, V., Mohseni, M., Stams, T., Buhrlage, S. J., Stegmaier, K., LaMarche, M. J., et al. (2017) · Bioorganic & Medicinal Chemistry · doi:10.1016/j.bmc.2017.10.025 · Cited by 51 · see citing works
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Fedele, C., Li, S., Teng, K. W., Foster, C. J. R., Peng, D., Ran, H., Mita, P., Geer, M. J., Hattori, T., Koide, A., et al. (2021) · Journal of Experimental Medicine · doi:10.1084/jem.20201414 · Cited by 265 · see citing works
Phase Separation of Disease-Associated SHP2 Mutants Underlies MAPK Hyperactivation
Zhu, G., Xie, J., Kong, W., Xie, J., Li, Y., Du, L., Zheng, Q., Sun, L., Guan, M., Li, H., et al. (2020) · Cell · doi:10.1016/j.cell.2020.09.002 · Cited by 267 · see citing works
Chasing molecular glue degraders: screening approaches
Domostegui, A., Nieto-Barrado, L., Perez-Lopez, C., & Mayor-Ruiz, C. (2022) · Chemical Society Reviews · doi:10.1039/d2cs00197g · Cited by 200 · see citing works
Kerr, D. L., Haderk, F., & Bivona, T. G. (2021) · Current Opinion in Chemical Biology · doi:10.1016/j.cbpa.2020.11.007 · Cited by 124 · see citing works
Song, Y., Zhao, M., Zhang, H., & Yu, B. (2022) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2021.107966 · Cited by 125 · see citing works
A comprehensive review of SHP2 and its role in cancer
Asmamaw, M. D., Shi, X.-J., Zhang, L.-R., & Liu, H.-M. (2022) · Cellular Oncology · doi:10.1007/s13402-022-00698-1 · Cited by 119 · see citing works
Targeted Degradation of the Oncogenic Phosphatase SHP2
Vemulapalli, V., Donovan, K. A., Seegar, T. C. M., Rogers, J. M., Bae, M., Lumpkin, R. J., Cao, R., Henke, M. T., Ray, S. S., Fischer, E. S., et al. (2021) · Biochemistry · doi:10.1021/acs.biochem.1c00377 · Cited by 43 · see citing works
Self-citationZhang, R.-Y., Yu, Z.-H., Chen, L., Walls, C. D., Zhang, S., Wu, L., & Zhang, Z.-Y. (2020) · Journal of Biological Chemistry · doi:10.1074/jbc.ra119.010274 · Cited by 22 · see citing works
- Authors
- LaRochelle, J. R., Fodor, M., Vemulapalli, V., Mohseni, M., Wang, P., Stams, T., LaMarche, M. J., Chopra, R., Acker, M. G., & Blacklow, S. C.
- Affiliations
- Harvard University (US)
- Corresponding author
- Acker, Michael G.
- Blacklow, Stephen C.
- ORCID
- Venue
- Nature Communications
- Published
- 2018-10-30
- Volume
- 9
- Issue
- 1
- Pages
- 4508-4508
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC6207684
- OpenAlex
- W2898146177
- Cited by
- 167
- References
- 31
- Citations by year
- 2026: 26 · 2025: 21 · 2024: 22 · 2023: 29 · 2022: 20 · 2021: 21 · 2020: 19 · 2019: 9
- FWCI
- 4.62
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, other-oa)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- The Novartis Repository (Novartis) (submittedVersion)
- OSTI OAI (U.S. Department of Energy Office of Scientific and Technical Information) (submittedVersion)
- Funders
- U.S. Department of Energy (DE‐ AC02‐06CH11357, AC02‐06CH11357, 06CH11357, DE-AC02-)
- American Cancer Society (128126)
- Dana-Farber Cancer Institute
- Industrial Macromolecular Crystallography Association Collaborative Access Team (DE-AC02-06CH11357)
- National Institutes of Health (DE-AC02–06CH11357, GM103622)
- Office of Science (AC02‐06CH11357, DE-AC02, 06CH11357, DE-AC02-06CH11357)
- National Cancer Institute (R35CA220340)
- National Institute of General Medical Sciences (P41GM103622, DE-AC02-06CH11357, GM103622)
- Argonne National Laboratory (P41 GM103622, DE- AC02-06-CH11357, DE-AC02, AC02–06CH11357, GM103622, 06CH11357)
- 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 › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Keywords
- SHP2, PTPN11, oncogenic mutations, SHP099, allosteric inhibition, protein tyrosine phosphatase, protein structure, hematologic cancer, oncogenic signaling
- MeSH terms
- Allosteric Regulation, Humans, Mutation, Piperidines, Protein Conformation, Pyrimidines, Oncogene Proteins, Protein Tyrosine Phosphatase, Non-Receptor Type 11
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