SHP2 sails from physiology to pathology
Abstract
Over the two past decades, mutations of the PTPN11 gene, encoding the ubiquitous protein tyrosine phosphatase SHP2 (SH2 domain-containing tyrosine phosphatase 2), have been identified as the causal factor of several developmental diseases (Noonan syndrome (NS), Noonan syndrome with multiple lentigines (NS-ML), and metachondromatosis), and malignancies (juvenile myelomonocytic leukemia). SHP2 plays essential physiological functions in organism development and homeostasis maintenance by regulating fundamental intracellular signaling pathways in response to a wide range of growth factors and hormones, notably the pleiotropic Ras/Mitogen-Activated Protein Kinase (MAPK) and the Phosphoinositide-3 Kinase (PI3K)/AKT cascades. Analysis of the biochemical impacts of PTPN11 mutations first identified both loss-of-function and gain-of-function mutations, as well as more subtle defects, highlighting the major pathophysiological consequences of SHP2 dysregulation. Then, functional genetic studies provided insights into the molecular dysregulations that link SHP2 mutants to the development of specific traits of the diseases, paving the way for the design of specific therapies for affected patients. In this review, we first provide an overview of SHP2's structure and regulation, then describe its molecular roles, notably its functions in modulating the Ras/MAPK and PI3K/AKT signaling pathways, and its physiological roles in organism development and homeostasis. In the second part, we descri…
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
SHP2 function is not restricted to IL-6-induced signalling; SHP2 is also a major regulator of signalling induced by other cytokines and growth factors.
“SHP2 function is not restricted to IL-6-induced signalling but SHP2 is also a major regulator of signalling induced by other cytokines and growth factors [48].”
From The tyrosine phosphatase SHP2 increases robustness and information transfer within IL-6-induced JAK/STAT signalling (2021) · cites this paper as [48]
Cites
Finding of Rare Disease Genes (FORGE) Canada Consortium, Rivière, J.-B., Mirzaa, G. M., O'Roak, B. J., Beddaoui, M., Alcantara, D., Conway, R. L., St-Onge, J., Schwartzentruber, J. A., Gripp, K. W., et al. (2012) · Nature Genetics · doi:10.1038/ng.2331 · Cited by 741 · see citing works
Diversity and functional consequences of germline and somatic PTPN11 mutations in human disease
Tartaglia, M., Martinelli, S., Stella, L., Bocchinfuso, G., Flex, E., Cordeddu, V., Zampino, G., van der Burgt, I., Palleschi, A., Petrucci, T. C., et al. (2006) · The American Journal of Human Genetics · doi:10.1086/499925 · Cited by 415 · see citing works
Protein-tyrosine-phosphatase SHPTP2 couples platelet-derived growth factor receptor beta to Ras.
Bennett, A. M., Tang, T. L., Sugimoto, S., Walsh, C. T., & Neel, B. G. (1994) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.91.15.7335 · Cited by 397 · see citing works
Lu, W., Gong, D., Bar-Sagi, D., & Cole, P. A. (2001) · Molecular Cell · doi:10.1016/s1097-2765(01)00369-0 · Cited by 268 · see citing works
PTP1B and SHP2 in POMC neurons reciprocally regulate energy balance in mice
Banno, R., Zimmer, D., De Jonghe, B. C., Atienza, M., Rak, K., Yang, W., & Bence, K. K. (2010) · Journal of Clinical Investigation · doi:10.1172/jci39620 · Cited by 214 · see citing works
The Phosphatase SHP2 Regulates the Spacing Effect for Long-Term Memory Induction
Pagani, M. R., Oishi, K., Gelb, B. D., & Zhong, Y. (2009) · Cell · doi:10.1016/j.cell.2009.08.033 · Cited by 157 · see citing works
Perkins, L. A., Johnson, M. R., Melnick, M. B., & Perrimon, N. (1996) · Developmental Biology · doi:10.1006/dbio.1996.0285 · Cited by 114 · see citing works
Transgenic Drosophila models of Noonan syndrome causing PTPN11 gain-of-function mutations
Oishi, K., Gaengel, K., Krishnamoorthy, S., Kamiya, K., Kim, I.-K., Ying, H., Weber, U., Perkins, L. A., Tartaglia, M., Mlodzik, M., et al. (2006) · Human Molecular Genetics · doi:10.1093/hmg/ddi471 · Cited by 81 · see citing works
Development of Diabesity in Mice with Neuronal Deletion of Shp2 Tyrosine Phosphatase
Krajewska, M., Banares, S., Zhang, E. E., Huang, X., Scadeng, M., Jhala, U. S., Feng, G.-S., & Krajewski, S. (2008) · The American Journal of Pathology · doi:10.2353/ajpath.2008.070594 · Cited by 72 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
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
Adachi, Y., Ito, K., Hayashi, Y., Kimura, R., Tan, T. Z., Yamaguchi, R., & Ebi, H. (2020) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-20-2077 · Cited by 249 · see citing works
SHP2 inhibition triggers anti-tumor immunity and synergizes with PD-1 blockade
Zhao, M., Guo, W., Wu, Y., Yang, C., Zhong, L., Deng, G., Zhu, Y., Liu, W., Gu, Y., Lu, Y., et al. (2019) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2018.08.009 · Cited by 190 · see citing works
Shp-2 Is Dispensable for Establishing T Cell Exhaustion and for PD-1 Signaling In Vivo
Rota, G., Niogret, C., Dang, A. T., Barros, C. R., Fonta, N. P., Alfei, F., Morgado, L., Zehn, D., Birchmeier, W., Vivier, E., et al. (2018) · Cell Reports · doi:10.1016/j.celrep.2018.03.026 · Cited by 155 · 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
Kostallari, E., Hirsova, P., Prasnicka, A., Verma, V. K., Yaqoob, U., Wongjarupong, N., Roberts, L. R., & Shah, V. H. (2018) · Hepatology · doi:10.1002/hep.29803 · Cited by 111 · see citing works
Fiebelkow, J., Guendel, A., Guendel, B., Mehwald, N., Jetka, T., Komorowski, M., Waldherr, S., Schaper, F., & Dittrich, A. (2021) · Cell Communication and Signaling · doi:10.1186/s12964-021-00770-7 · Cited by 53 · see citing works
“SHP2 function is not restricted to IL-6-induced signalling but SHP2 is also a major regulator of signalling induced by other cytokines and growth factors [48].”
BackgroundZhang, 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
- Tajan, M., de Rocca Serra, A., Valet, P., Edouard, T., & Yart, A.
- Affiliations
- Université Toulouse III - Paul Sabatier (FR)
- Corresponding author
- Yart, Armelle
- Venue
- European Journal of Medical Genetics
- Publisher
- Elsevier BV
- Published
- 2015-10
- Volume
- 58
- Issue
- 10
- Pages
- 509-525
- ISSN
- 1769-7212 (ISSN-L)
- OpenAlex
- W1674292201
- Cited by
- 232
- References
- 9
- Citations by year
- 2026: 11 · 2025: 13 · 2024: 18 · 2023: 36 · 2022: 28 · 2021: 32 · 2020: 32 · 2019: 18 · 2018: 19 · 2017: 18 · 2016: 7
- FWCI
- 1.42
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- European Journal of Medical Genetics (publishedVersion)
- PubMed (publishedVersion)
- Funders
- INSERM (ANR-06-MRAR-031-01, R09001BP)
- Ministère de l'Education Nationale de la Recherche et de la Technologie (France)
- GIS-Maladies Rares
- Agence Nationale de la Recherche
- E-Rare (NSEuroNet)
- Institut National du Cancer
- 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 › Immunodeficiency and Autoimmune Disorders
- Keywords
- SHP2, PTPN11, Noonan syndrome, Noonan syndrome with multiple lentigines, juvenile myelomonocytic leukemia, RAS/MAPK pathway, PI3K/Akt signaling, loss-of-function mutations, gain-of-function mutations, developmental disorders, disease pathophysiology, therapeutic target
- MeSH terms
- Amino Acid Sequence, Animals, Humans, Molecular Sequence Data, Mutation, Noonan Syndrome, Signal Transduction, Protein Tyrosine Phosphatase, Non-Receptor Type 11
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
