Molecular Basis of Gain-of-Function LEOPARD Syndrome-Associated SHP2 Mutations

Yu, Zhi-Hong; Zhang, Ruo-Yu; Walls, Chad D.; Chen, Lan; Zhang, Sheng; Wu, Li; Liu, Sijiu; Zhang, Zhong-Yin

doi:10.1021/bi5002695

Cited by 90Protein Tyrosine PhosphatasesProtein Kinase Regulation and GTPase SignalingGenomics and Rare Diseases

Molecular Basis of Gain-of-Function LEOPARD Syndrome-Associated SHP2 Mutations

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Yu, Zhi-Hong, Zhang, Ruo-Yu, Walls, Chad D., Chen, Lan, Zhang, Sheng, Wu, Li, Liu, Sijiu, Zhang, Zhong-Yin·2014·Biochemistry

DOI 10.1021/bi5002695PMC PMC4081049

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Abstract

The Src homology 2 (SH2) domain-containing protein tyrosine phosphatase 2 (SHP2) is a critical signal transducer downstream of growth factors that promotes the activation of the RAS-ERK1/2 cascade. In its basal state, SHP2 exists in an autoinhibited closed conformation because of an intramolecular interaction between its N-SH2 and protein tyrosine phosphatase (PTP) domains. Binding to pTyr ligands present on growth factor receptors and adaptor proteins with its N-SH2 domain localizes SHP2 to its substrates and frees the active site from allosteric inhibition. Germline mutations in SHP2 are known to cause both Noonan syndrome (NS) and LEOPARD syndrome (LS), two clinically similar autosomal dominant developmental disorders. NS-associated SHP2 mutants display elevated phosphatase activity, while LS-associated SHP2 mutants exhibit reduced catalytic activity. A conundrum in how clinically similar diseases result from mutations to SHP2 that have opposite effects on this enzyme’s catalytic functionality exists. Here we report a comprehensive investigation of the kinetic, structural, dynamic, and biochemical signaling properties of the wild type as well as all reported LS-associated SHP2 mutants. The results reveal that LS-causing mutations not only affect SHP2 phosphatase activity but also induce a weakening of the intramolecular interaction between the N-SH2 and PTP domains, leading to mutants that are more readily activated by competing pTyr ligands. Our data also indicate that the residual phosphatase activity associated with the LS SHP2 mutant is required for enhanced ERK1/2 activation. Consequently, catalytically impaired SHP2 mutants could display gain-of-function properties because of their ability to localize to the vicinity of substrates for longer periods of time, thereby affording the opportunity for prolonged substrate turnover and sustained RAS-ERK1/2 activation.

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Loss-of-function as well as gain-of-function mutations and/or overexpression of SHP2 are found in various diseases such as different cancer types, Noonan syndrome, and LEOPARD syndrome.
“Loss-of-function as well as gain-of-function mutations and/or overexpression of SHP2 are found in various diseases such as different cancer types [49], Noonan- [50], and LEOPARD-syndrome [51].”
From The tyrosine phosphatase SHP2 increases robustness and information transfer within IL-6-induced JAK/STAT signalling (2021) · cites this paper as [51]

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Diverse driving forces underlie the invariant occurrence of the T42A, E139D, I282V and T468M SHP2 amino acid substitutions causing Noonan and LEOPARD syndromes
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Transgenic Drosophila models of Noonan syndrome causing PTPN11 gain-of-function mutations
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The Caenorhabditis elegans SH2 domain-containing protein tyrosine phosphatase PTP-2 participates in signal transduction during oogenesis and vulval developmentPreprint
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Altering the Nucleophile Specificity of a Protein-tyrosine Phosphatase-catalyzed Reaction
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Impaired Transition State Complementarity in the Hydrolysis of O-Arylphosphorothioates by Protein-Tyrosine Phosphatases
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How do Shp2 mutations that oppositely influence its biochemical activity result in syndromes with overlapping symptoms?
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LEOPARD Syndrome: A Variant of Noonan Syndrome Strongly Associated With Hypertrophic Cardiomyopathy
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Hof P.; Pluskey S.; Dhe-Paganon S.; Eck M. J.; Shoelson S. E. (1998) Crystal structure of the tyrosine phosphatase SHP2. Cell 92, 441– 450. 9491886

Sorted by citations

Phase Separation of Disease-Associated SHP2 Mutants Underlies MAPK Hyperactivation
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Applications of Hydrogen/Deuterium Exchange MS from 2012 to 2014
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Double-edged roles of protein tyrosine phosphatase SHP2 in cancer and its inhibitors in clinical trials
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Therapeutic potential of targeting SHP2 in human developmental disorders and cancers
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Recent advances in understanding the role of protein-tyrosine phosphatases in development and disease
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Structural and Functional Consequences of Three Cancer-Associated Mutations of the Oncogenic Phosphatase SHP2
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Role of SHP2 in hematopoiesis and leukemogenesis
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Growth patterns of patients with Noonan syndrome: correlation with age and genotype
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The tyrosine phosphatase SHP2 increases robustness and information transfer within IL-6-induced JAK/STAT signalling
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“Loss-of-function as well as gain-of-function mutations and/or overexpression of SHP2 are found in various diseases such as different cancer types [49], Noonan- [50], and LEOPARD-syndrome [51].”
Background
Targeting Oncogenic Src Homology 2 Domain-Containing Phosphatase 2 (SHP2) by Inhibiting Its Protein–Protein Interactions
Bobone, S., Pannone, L., Biondi, B., Šolman, M., Flex, E., Canale, V. C., Calligari, P. A., Faveri, C. D., Gandini, T., Quercioli, A., et al. (2021) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.1c01371 · Cited by 51 · see citing works
Low-dose dasatinib rescues cardiac function in Noonan syndrome
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Crystallographic landscape of SHP2 provides molecular insights for SHP2 targeted drug discovery
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Combination Approaches to Target PD-1 Signaling in Cancer
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RASopathy Gene Mutations in Melanoma
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Discovery of 6-[(3 S ,4 S )-4-Amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl]-3-(2,3-dichlorophenyl)-2-methyl-3,4-dihydropyrimidin-4-one (IACS-15414), a Potent and Orally Bioavailable SHP2 Inhibitor
Czakó, B., Sun, Y., McAfoos, T. J., Cross, J. B., Leonard, P. G., Burke, J. P., Carroll, C. L., Feng, N., Harris, A. L., Jiang, Y., et al. (2021) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.1c01132 · Cited by 29 · see citing works
Integrative genetic analysis of mouse and human AML identifies cooperating disease alleles
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The loops of the N-SH2 binding cleft do not serve as allosteric switch in SHP2 activation
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Mechanistic insights explain the transforming potential of the T507K substitution in the protein-tyrosine phosphatase SHP2
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Low-dose Dasatinib Ameliorates Hypertrophic Cardiomyopathy in Noonan Syndrome with Multiple Lentigines
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Protein tyrosine phosphatases in cardiac physiology and pathophysiology
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Tyrosyl phosphorylation of PZR promotes hypertrophic cardiomyopathy in PTPN11-associated Noonan syndrome with multiple lentigines
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Emerging chemical scaffolds with potential SHP2 phosphatase inhibitory capabilities – A comprehensive review
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DephosSite: a machine learning approach for discovering phosphotase-specific dephosphorylation sites
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Deep mutational scanning of the multi-domain phosphatase SHP2 reveals mechanisms of regulation and pathogenicity
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Phase-Separated Subcellular Compartmentation and Related Human Diseases
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New insights into the important roles of phase seperation in the targeted therapy of lung cancer
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Bivalent target-binding bioPROTACs induce potent degradation of oncogenic SHP2
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Role of PTPN11 (SHP2) in Cancer
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Response of NF1-Mutated Melanoma to an MEK Inhibitor
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Mutations in PTPN11 could lead to a congenital myasthenic syndrome phenotype: a Noonan syndrome case series
Pugliese, A., Marina, A. D., Estephan, E. D. P., Zanoteli, E., Roos, A., Schara, U., Hentschel, A., Azuma, Y., Töpf, A., Thompson, R., et al. (2023) · Journal of Neurology · doi:10.1007/s00415-023-12070-w · Cited by 13 · see citing works
Potential Reuse of Oncology Drugs in the Treatment of Rare Diseases
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Modeling (not so) rare developmental disorders associated with mutations in the protein-tyrosine phosphatase SHP2
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Probing the Dynamic Mechanism of Uncommon Allosteric Inhibitors Optimized to Enhance Drug Selectivity of SHP2 with Therapeutic Potential for Cancer Treatment
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Endothelial Shp2 deficiency controls alternative activation of macrophage preventing radiation-induced lung injury through notch signaling
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Quantitation of autoinhibitory defects in pathogenic SHP2 mutants by differential scanning fluorimetry
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A small molecule inhibitor targeting SHP2 mutations for the lung carcinoma
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Self-citation
Roles for a lipid phosphatase in the activation of its opposing lipid kinase
Strunk, B. S., Steinfeld, N., Lee, S., Jin, N., Muñoz-Rivera, C., Meeks, G., Thomas, A., Akemann, C., Mapp, A. K., MacGurn, J. A., et al. (2020) · Molecular Biology of the Cell · doi:10.1091/mbc.e18-09-0556 · Cited by 12 · see citing works
Complex Roles of PTPN11/SHP2 in Carcinogenesis and Prospect of Targeting SHP2 in Cancer Therapy
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Shp2–Mitogen-Activated Protein Kinase Signaling Drives Proliferation during Zebrafish Embryo Caudal Fin Fold Regeneration
Hale, A. J., & den Hertog, J. (2017) · Molecular and Cellular Biology · doi:10.1128/mcb.00515-17 · Cited by 10 · see citing works
SHP2 as a primordial epigenetic enzyme expunges histone H3 pTyr-54 to amend androgen receptor homeostasis
Chouhan, S., Sridaran, D., Weimholt, C., Luo, J. R., Li, T., Hodgson, M. C., Santos, L. N., Sommer, S. L., Fang, B., Koomen, J. M., et al. (2024) · Nature Communications · doi:10.1038/s41467-024-49978-4 · Cited by 9 · see citing works
Identification of a PTPN11 hot spot mutation in a child with atypical LEOPARD syndrome
Zhang, J., Shen, J., Cheng, R., Ni, C., Liang, J., Li, M., & Yao, Z. (2016) · Molecular Medicine Reports · doi:10.3892/mmr.2016.5547 · Cited by 9 · see citing works
The Cell-Specific Role of SHP2 in Regulating Bone Homeostasis and Regeneration Niches
Zhang, J., Ye, C., Zhu, Y., Wang, J., & Liu, J. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24032202 · Cited by 8 · see citing works
SHP2 genetic variants in NSML-associated RASopathies disrupt the PZR–IRX transcription factor signaling axis
Perla, S., Stiegler, A. L., Yi, J.-S., Enyenihi, L., Zhang, L., Riaz, M., An, E., Qyang, Y., Boggon, T. J., & Bennett, A. M. (2025) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2503631122 · Cited by 7 · see citing works
Targeting a Pathogenic Cysteine Mutation: Discovery of a Specific Inhibitor of Y279C SHP2
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A novel stop-gain pathogenic variant in FLT4 and a nonsynonymous pathogenic variant in PTPN11 associated with congenital heart defects
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E76K Mutation Promotes SHP2 Activation by Rewiring Allosteric Networks That Drives Conformational Transitions
Zhao, D.-R., Liu, M.-T., Duan, H., Zhu, J.-Y., Yang, L.-Q., & Sang, P. (2025) · Journal of Chemical Information and Modeling · doi:10.1021/acs.jcim.5c01201 · Cited by 5 · see citing works
Genetic and phenotypic heterogeneity of multiple lentigines and precise diagnosis in four Chinese families with multiple lentigines
Guo, K., Liu, J., Zhang, R., Wang, R., Ma, D., & Zhang, X. (2023) · Pigment Cell & Melanoma Research · doi:10.1111/pcmr.13086 · Cited by 6 · see citing works
Self-citation
Compound heterozygosity for PTPN11 variants in a subject with Noonan syndrome provides insights into the mechanism of SHP2 ‐related disorders
Lorca, R., Pannone, L., Cuesta‐Llavona, E., Bocchinfuso, G., Rodríguez-Reguero, J., Carpentieri, G., Hernando, I., Flex, E., Tartaglia, M., Coto, E., et al. (2020) · Clinical Genetics · doi:10.1111/cge.13904 · Cited by 6 · see citing works
An Assessment of the Therapeutic Landscape for the Treatment of Heart Disease in the RASopathies
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Proximity-labeling proteomics reveals remodeled interactomes and altered localization of pathogenic SHP2 variants
van Vlimmeren, A. E., Tang, L. C., Jiang, Z., Iyer, A., Voleti, R., Krismer, K., Gaublomme, J. T., Jovanović, M., & Shah, N. H. (2025) · EMBO Reports · doi:10.1038/s44319-025-00674-4 · Cited by 5 · see citing works
A Novel Gain-of-Signal Assay to Detect Targeted Protein Degradation
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Paternally Inherited Noonan Syndrome Caused by a PTPN11 Variant May Exhibit Mild Symptoms: A Case Report and Literature Review
Han, J. Y., & Park, J. (2024) · Genes · doi:10.3390/genes15040445 · Cited by 5 · see citing works
Cross the Undruggable Barrier, the Development of SHP2 Inhibitors: From Catalytic Site Inhibitors to Allosteric Inhibitors
Guo, Y. L., Xu, Y., Dong, X., & Zhang, J. (2021) · ChemistrySelect · doi:10.1002/slct.202100186 · Cited by 5 · see citing works
High-quality SNPs from genic regions highlight introgression patterns among European white oaks (Quercus petraea and Q. robur)Preprint
Lang, T., Abadie, P., Léger, V., Decourcelle, T., Frigerio, J.-M., Burban, C., Bodénès, C., Guichoux, E., Provost, G. L., Robin, C., et al. (2019) · HAL · doi:10.5061/dryad.4mw6m906j · Cited by 5 · see citing works
Deep mutational scanning of a multi-domain signaling protein reveals mechanisms of regulation and pathogenicityPreprint
Jiang, Z., van Vlimmeren, A. E., Karandur, D., Semmelman, A., & Shah, N. H. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.05.13.593907 · Cited by 5 · see citing works
SHP2: A Redox-Sensitive Regulator Linking Immune Checkpoint Inhibitor Therapy to Cancer Treatment and Vascular Risk
Moreno, S. F. L., Lenz, S. A., Casso-Chapa, B., Paniagua-Bojorges, A., Kim, J. H., Palaskas, N. L., Nead, K. T., Samanthapudi, V. S. K., Mejia, G. F., Hoang, O. N., et al. (2025) · Antioxidants · doi:10.3390/antiox14121388 · Cited by 4 · see citing works
Investigating the reason for loss-of-function of Src homology 2 domain-containing protein tyrosine phosphatase 2 (SHP2) caused by Y279C mutation through molecular dynamics simulation
Liu, W., Wang, R., Li, W., Rong, M., Liu, C.-L., Ma, Y., & Wang, R. (2019) · Journal of Biomolecular Structure and Dynamics · doi:10.1080/07391102.2019.1634641 · Cited by 4 · see citing works
Noonan Syndrome with Multiple Lentigines
Hodgson, M. C., Chennappan, S., & Kontaridis, M. I. (2024) · Springer eBooks · doi:10.1007/978-3-031-62945-7_5 · Cited by 3 · see citing works
Co‐occurrence of hypertrophic cardiomyopathy and juvenile myelomonocytic leukemia in a neonate with Noonan syndrome, leading to premature death
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Structural and Mechanistic Insights into LEOPARD Syndrome-Associated SHP2 Mutations
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Authors: Yu, Z.-H., Zhang, R.-Y., Walls, C. D., Chen, L., Zhang, S., Wu, L., Liu, S., & Zhang, Z.-Y.
Affiliations: Indiana University Indianapolis (US)
Indiana University School of Medicine , , 635 Barnhill Drive , , ,
Corresponding author: Zhang, Zhong-Yin
ORCID: Walls, Chad D.
Chen, Lan
Zhang, Sheng
Wu, Li
Zhang, Zhong-Yin
Venue: Biochemistry
Publisher: American Chemical Society (ACS)
Published: 2014-06-08
Volume: 53
Issue: 25
Pages: 4136-4151
ISSN: 0006-2960 (ISSN-L)
1520-4995
DOI: 10.1021/bi5002695
PMC: PMC4081049
OpenAlex: W2169365832
Cited by: 87
References: 93
Citations by year: 2026: 9 · 2025: 8 · 2024: 6 · 2023: 9 · 2022: 10 · 2021: 11 · 2020: 8 · 2019: 2 · 2018: 5 · 2017: 5 · 2016: 10 · 2015: 3 · 2014: 1
FWCI: 2.60
Type: journal article
Language: en
Open access: hybrid
doi.org
Licence: other-oa
pubs.acs.org/page/policy/authorchoice_termsofuse.html (vor, 365 d)
Locations: Biochemistry (publishedVersion, other-oa)
Europe PMC (PubMed Central) (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
IUScholarWorks (Indiana University) (submittedVersion, other-oa)
Publisher
Funders: National Institutes of Health
National Cancer Institute (R01CA69202, R01CA069202, P30CA082709)
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 › Genetics › Genomics and Rare Diseases
Keywords: SHP2, LEOPARD syndrome, Noonan syndrome, gain-of-function mutations, protein tyrosine phosphatase, allosteric inhibition, phosphatase activity, protein localization, substrate turnover
MeSH terms: Enzyme Activation, Humans, Kinetics, Models, Molecular, Mutation, Protein Conformation, src Homology Domains, Mitogen-Activated Protein Kinase 1, LEOPARD Syndrome, Mitogen-Activated Protein Kinase 3, Protein Tyrosine Phosphatase, Non-Receptor Type 11, HEK293 Cells

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Molecular Basis of Gain-of-Function LEOPARD Syndrome-Associated SHP2 Mutations

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