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.
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“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]
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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
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Combination strategies with PD-1/PD-L1 blockade: current advances and future directions
Yi, M., Zheng, X., Niu, M., Zhu, S., Ge, H., & Wu, K. (2022) · Molecular Cancer · doi:10.1186/s12943-021-01489-2 · Cited by 1,445
Small molecule inhibitors targeting the cancers
Liu, G., Chen, T., Zhang, X., Ma, X., & Shi, H. (2022) · MedComm · doi:10.1002/mco2.181 · Cited by 212
Progress on Ras/MAPK Signaling Research and Targeting in Blood and Solid Cancers
Dillon, M., Lopez, A. R., Lin, E., Sales, D., Perets, R., & Jain, P. (2021) · Cancers · doi:10.3390/cancers13205059 · Cited by 175
Pan, J., Zhou, L., Zhang, C., Xu, Q., & Sun, Y. (2022) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-022-01038-3 · Cited by 118
Strategies Targeting Protein Tyrosine Phosphatase SHP2 for Cancer Therapy
Song, Y., Wang, S., Zhao, M., Yang, X., & Yu, B. (2022) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.1c02008 · Cited by 101
Self-citation
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
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