The DOI matches its Crossref record; 150 of the 151 references it cites were found in a registry or an index.
Double-edged roles of protein tyrosine phosphatase SHP2 in cancer and its inhibitors in clinical trials
Abstract
Phosphorylation is a reversible post-translational modification regulated by phosphorylase and dephosphorylase to mediate important cellular events. Src homology-2-containing protein tyrosine phosphatase 2 (SHP2) encoded by PTPN11 is the first identified oncogenic protein in protein tyrosine phosphatases family. Serving as a convergent node, SHP2 is involved in multiple cascade signaling pathways including Ras-Raf-MEK-ERK, PI3K-AKT, JAK-STAT and PD-1/PD-L1 pathways. Especially, the double-edged roles of SHP2 based on the substrate specificity in various biological contexts dramatically increase the effect complexity in different SHP2-associated diseases. Evidences suggest that by collaborating with other mutations in associated pathways, dysregulation of SHP2 contributes to the pathogenesis of different cancers, making SHP2 a promising therapeutic target for cancer treatment. SHP2 can either act as oncogenic factor or tumor suppressor in different diseases, and both the conserved catalytic dephosphorylation mechanism and the unique allosteric regulation mechanism of SHP2 provide opportunities for the development of SHP2 inhibitors and activators. To date, several small-molecule SHP2 inhibitors have advanced into clinical trials for mono- or combined therapy of cancers. Moreover, SHP2 activators and proteolysis-targeting chimera (PROTAC)-based degraders also display therapeutic promise. In this review, we comprehensively summarize the overall structures, regulation mechanisms, double-edged roles of SHP2 in both physiological and carcinogenic pathways, and SHP2 inhibitors in clinical trials. SHP2 activators and degraders are also briefly discussed. This review aims to provide in-depth understanding of the biological roles of SHP2 and highlight therapeutic potential of targeting SHP2.
Overview
Integrity signals
Registry
Cites
Statistics
Verification
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?
In the citing paper
“As the convergent node of MAPK, PI3K-AKT, JAK-STAT, and PD-1 pathways, SHP2 widely regulates multiple cancer-associated processes such as cell survival and immune escape [251].”
From Combination strategies with PD-1/PD-L1 blockade: current advances and future directions (2022) · cites this paper as [251]
Citations
Cites
The blockade of immune checkpoints in cancer immunotherapy
Pardoll, D. M. (2012) · Nature Reviews Cancer · doi:10.1038/nrc3239 · Cited by 13,838
The phosphoinositide 3-kinase pathway
Cantley, L. C. (2002) · Science · doi:10.1126/science.296.5573.1655 · Cited by 5,621
Protein kinases and phosphatases: The Yin and Yang of protein phosphorylation and signaling
Hunter, T. R. (1995) · Cell · doi:10.1016/0092-8674(95)90405-0 · Cited by 2,961
Phosphatidylinositol-3-OH kinase direct target of Ras
Rodriguez-Viciana, P., Warne, P. H., Dhand, R., Vanhaesebroeck, B., Gout, I., Fry, M. J., Waterfield, M. D., & Downward, J. (1994) · Nature · doi:10.1038/370527a0 · Cited by 1,954
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
T cell costimulatory receptor CD28 is a primary target for PD-1–mediated inhibition
Hui, E., Cheung, J., Zhu, J., Su, X., Taylor, M. J., Wallweber, H. A., Sasmal, D. K., Huang, J., Kim, J. M., Mellman, I., et al. (2017) · Science · doi:10.1126/science.aaf1292 · Cited by 1,689
Ardito, F., Giuliani, M., PERRONE, D., Troiano, G., & Muzio, L. L. (2017) · International Journal of Molecular Medicine · doi:10.3892/ijmm.2017.3036 · Cited by 1,437
Immune checkpoint signaling and cancer immunotherapy
He, X., & Xu, C. (2020) · Cell Research · doi:10.1038/s41422-020-0343-4 · Cited by 1,431
Regulation of JAK–STAT signalling in the immune system
Shuai, K., & Liu, B. (2003) · Nature reviews. Immunology · doi:10.1038/nri1226 · Cited by 1,410
Yokosuka, T., Takamatsu, M., Kobayashi-Imanishi, W., Hashimoto-Tane, A., Azuma, M., & Saito, T. (2012) · Journal of Experimental Medicine · doi:10.1084/jem.20112741 · Cited by 1,161
Cited by
Sorted by citations
Items 101–127 of 127
Molecular Docking Study of Oxido-Vanadium Complexes with Proteins Involved in Breast Cancer
Noriega, L., Castro, M. E., Caballero, N. A., Merino, G., & Meléndez, F. J. (2023) · Lecture notes in networks and systems · doi:10.1007/978-981-99-1916-1_12
Therapeutic Effect of Shp2 Inhibition Combined with Regorafenib in Advanced Colorectal CancerPreprint
Han, X., Wang, W., Zhang, W., Zhu, L., Xu, L., Li, X., Xu, Q., Guo, W., & Gu, Y. (2023) · SSRN Electronic Journal · doi:10.2139/ssrn.4534174
Huang, R., Zhang, Y.-T., Lin, Y., Pang, R.-L., Yang, Z., & Zhao, W. (2023) · Pharmacogenomics and Personalized Medicine · doi:10.2147/pgpm.s420254
Small Molecule SHP2 Inhibitor LXQ‐217 Affects Lung Cancer Cell Proliferation in Vitro and in Vivo
Sun, H., Bai, X., Zhang, Y., Gao, Y., Dai, J., Xing, P., Zhu, J., Liu, R., Wang, Z., & Li, X. (2024) · Chemistry & Biodiversity · doi:10.1002/cbdv.202301610
Yay, F., & Ayan, D. (2024) · Computers in Biology and Medicine · doi:10.1016/j.compbiomed.2024.109304
Zhang, Y., Wang, H., Wei, Y., Pan, Y., Song, X., Shi, T., Shao, J., Yu, L., Liu, B., Wang, Y., et al. (2025) · eLife · doi:10.7554/elife.104060.1
Zhang, Y., Wang, H., Wei, Y., Pan, Y., Song, X., Shao, J., Yu, L., Shi, T., & Wang, Y. (2025) · eLife · doi:10.7554/elife.104060
PRL-3: unveiling a new horizon in cancer therapy
Cao, Z., Mao, J., Huang, C.-Y., Wang, H., Wang, M., Wang, W., Zhou, Y., & Li, J. (2025) · Acta Pharmacologica Sinica · doi:10.1038/s41401-025-01563-1
Research Progress of SHP2 Modulator in Anti-Tumor Biological Mechanism
Guo, J. (2025) · BIO Web of Conferences · doi:10.1051/bioconf/202517402019
Targeting SHP2 for Cancer Treatment: Advances and Prospects
Song, Y., & Yu, B. (2025) · Springer eBooks · doi:10.1007/978-3-032-00771-1_256
Self-citationWang, S., Tong, J., Jin, B., Lei, Q., & Zheng, Q. (2025) · European journal of medical research · doi:10.1186/s40001-025-03103-3
Banerjee, J., Samanta, S., Afiadenyo, M., Ahmed, R., Das, S., Hasan, S. N., & Dash, S. K. (2025) · In Silico Pharmacology · doi:10.1007/s40203-025-00478-3
Discovery a plasiatine-based potent SHP2 activator as a potential anti-atherosclerotic agent
Ding, X., Geng, T., Li, Y., Pan, P., Li, Z., Li, Z., & Meng, X. (2025) · Chinese Chemical Letters · doi:10.1016/j.cclet.2025.112140
Structural insights into the binding modes of SHP2 allosteric inhibitors
Jama, M., Mosa, F. E. S., Overduin, M., & Barakat, K. (2026) · In Silico Pharmacology · doi:10.1007/s40203-025-00551-x
Wang, Y., Shao, X., Wang, M., Li, Z., Sun, Y., & Meng, X. (2026) · Bioorganic Chemistry · doi:10.1016/j.bioorg.2026.109573
Zhang, Y., Wang, H., Wei, Y., Pan, Y., Song, X., Shao, J., Yu, L., Shi, T., & Wang, Y. (2026) · eLife · doi:10.7554/elife.104060.2
Wan, X., Yi, C., Jia, T., Quan, D., Mo, C., Pan, Q., Qin, Y., Wang, T., Wen, S., & Qiang, Z. (2026) · Cytotechnology · doi:10.1007/s10616-026-00943-7
Pharmacocinétique / pharmacodynamie du dabrafenib et du trametinib dans les tumeurs solides
Balakirouchenane, D. (2023) · theses.fr (ABES) · doi:10.70675/59ba7d0fz7679z4b46z978ez24aeae7f339c
SHP2 negatively regulates TGF-β signaling by destabilizing the TGF-β type I receptor
Zhao, C., Yakymovych, I., Yakymovych, M., Xing, P., & Heldin, C. (2026) · Cell Communication and Signaling · doi:10.1186/s12964-026-03043-3
BindingDB (2024) · UC San Diego · doi:10.7270/q2wm1jwj
BindingDB Entry 50022804: Advances in SHP2 tunnel allosteric inhibitors and bifunctional molecules.
BindingDB (2026) · UC San Diego · doi:10.7270/q2v98dw4
BindingDB Entry 50016243: Strategies Targeting Protein Tyrosine Phosphatase SHP2 for Cancer Therapy.
BindingDB (2023) · UC San Diego · doi:10.7270/q2x92g9p
Tang, J., Cheng, Z., Xie, T., Zhuang, Y., Hu, H., Li, C., Wang, H., Feng, C., & Tu, C. (2026) · Biomarker Research · doi:10.1186/s40364-026-01032-9
Metadata
- Authors
- Song, Y., Zhao, M., Zhang, H., & Yu, B.
- Affiliations
- Peking University (CN)
- Zhengzhou University (CN)
- Corresponding author
- Yu, Bin
- Venue
- Pharmacology & Therapeutics
- Publisher
- Elsevier BV
- Published
- 2022-02
- Volume
- 230
- Pages
- 107966
- ISSN
- 0163-7258 (ISSN-L)
- OpenAlex
- W3193470707
- Cited by
- 125
- References
- 151
- Citations by year
- 2026: 12 · 2025: 32 · 2024: 30 · 2023: 24 · 2022: 25
- FWCI
- 2.18
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- Locations
- Pharmacology & Therapeutics (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Natural Science Foundation of China
- 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 › Cancer Research › Cancer Mechanisms and Therapy
- Keywords
- SHP2, PTPN11, protein tyrosine phosphatase, oncoprotein, tumor suppressor, cancer, SHP2 inhibitors, PROTAC degraders, allosteric regulation, RAS/MAPK pathway, PI3K/Akt signaling, JAK/STAT signaling, PD-1/PD-L1 pathway, small molecule inhibitors, clinical trials
- MeSH terms
- Enzyme Inhibitors, Humans, Neoplasms, Oncogenes, Signal Transduction, Phosphatidylinositol 3-Kinases, 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
