Protein Tyrosine Phosphatase SHP2 and Its Link to Cancer

Nike McCune '25 & Denil Joseph '26

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I. Introduction

SHP2 or Src homology 2 domain-containing protein tyrosine phosphatase 2 is a non-receptor protein tyrosine phosphatase (PTP) protein. It is a phosphatase, being heavily involved in a variety of cell signaling pathways including the PI3K/AKT, and JAK/STAT pathways. It is primarily responsible for its control over cell growth, proliferation, and differentiation, by means of the RAS/MAPK pathway, and its interactions with the growth factor receptors.

The activation of SHP2 by receptor tyrosine kinases or particular mutations are thought to induce an open conformation of SHP2. However, researchers are interested in the binding of inhibitor molecules to produce a closed conformation of SHP2 and potentially control its regulation of signaling pathways to prevent tumors (Shen et al., 2020). 

II. General Structure

SHP2 is a modular protein composed of two , a , and a . These domains work in concert to achieve SHP2's multifaceted functions. The N-SH2 and PTP domains can undergo large conformational changes, toggling between an inactive closed state and an active open state. In the closed state, the N-SH2 domain sits in the PTP catalytic cleft, blocking the active site. SHP2 transitions to an open upon binding phosphotyrosine peptides or acquisition of activating mutations, rotating the N-SH2 domain relative to the PTP domain.

Figure 1. Visual representations of the closed (top), open (bottom) and intermediate conformations of the SHP2 protein. (Darian et al., 2011)

III. Domain Interactions


The N-SH2 domain contains central β-sheets sandwiched between α-helices with a phosphotyrosine binding pocket. It regulates PTP activity through interactions centered around between the PTP domain and N-SH2, between Ala72, Gln506, Asp61, Ala461, Gly464, Gly60 and Gln510 (Wang et al., 2020). This blocks access to N-SH2's phosphotyrosine pocket and the PTP active site cleft.

The PTP domain acts as the catalytic core of SHP2, spanning about 270 amino acids, and is responsible for the dephosphorylation of tyrosine residues on target proteins. It contains multiple flexible loops that enable substrate binding and catalysis - the (residues 421-431) orients Asp425 to donate a proton, the (residues 458-465) houses the catalytic Cys459 and Arg465, and the (residues 501-507) positions Gln501 to activate a water nucleophile. , they promote phosphate hydrolysis, with Cys459 and Arg465 attacking the substrate phosphate then Asp425 and Gln501 coordinating to regenerate the enzyme and release the phosphate group.


Figure 2. Catalytic mechanism of SHP2 dephosphorylation activity. (A) Multiple steps in the reaction showing reversible substrate binding, phospho-cysteine intermediate formation, and regeneration of the enzyme. (B) Key residues within the PTP domain, including the WPD loop, P loop, and Q loop, that engage in phosphoester bond cleavage, formation of the phospho-enzyme intermediate, and phospho-thioester bond hydrolysis to complete substrate dephosphorylation. (Song et al., 2022)

The C-SH2 domain contributes to phosphotyrosine-dependent targeting of SHP2 by allowing for more specific binding of substrates, but does not directly participate in catalysis. The C-terminal tail functions as a versatile signaling hub and spans approximately 50 amino acids. It contains phosphorylatable , allowing it to orchestrate interactions with a diverse array of proteins involved in various signaling pathways.

IV. Mutations

Gain of function mutations in SHP2 proteins typically affect the interaction between the N-SH2 domain and the PTP catalytic domain, leading to constitutive activation of SHP2 phosphatase activity. In contrast, Loss of function mutations reduce SHP2 catalytic activity and impair downstream signaling. Specifically, the amino acid substitutions like and lead to disruption of the autoinhibited state of SHP2, exposing the catalytic site constantly. This leads to increased activity, driving aberrant Ras/Erk signaling and reactive oxygen species that contribute to uncontrolled proliferation and cancer progression. In contrast, mutations like and impair phosphatase activity through mechanisms like disrupting substrate binding, preventing downstream signaling important for normal cell differentiation and organ development.   

Figure 3. Structural differences in SHP2 protein complex conformations a result of E76K gain of function and Q510E loss of function mutations. (Dong et al., 2021)

Targeting mutant SHP2 signaling is a promising therapeutic strategy in affected cancers.

V. Cancer and Treatments

Due to its role in cell profiferation and growth, mutations in SHP2 and overexpression of the protein in general has been heavily linked to cancer, and is a point of interest in finding potential treatments and ways to prevent it. One way researchers have found to go about this is by targeting the protein with drugs to inhibit activity. This is done by creating drugs that will bind the catalytic site of SHP2,  promoting formation of the closed, inactive conformation. Specifically, the drug has seen promising results as an inhibitor of SHP2. Because the drugs are similar in structure, they bind similar residues within the enzyme. 

Figure 4. Comprehensive View of SHP2: (A) Illustration outlining SHP2's involvement in receptor tyrosine kinase (RTK) signaling. (B) X-ray crystallographic representations showcasing SHP2 in both open and closed states. (C) Depictions of pertinent SHP2 inhibitors currently undergoing clinical trials by researchers. (Taylor et al., 2023)

VI. References

Asmamaw, M. D., Shi, X., Zhang, L., & Liu, H. (2022). A comprehensive review of SHP2 and its role in cancer. Cellular Oncology, 45(5), 729–753. https://doi.org/10.1007/s13402-022-00698-1

Chen, Y. P., LaMarche, M. J., Chan, H. M., Fekkes, P., Garcı́a-Fortanet, J., Acker, M. G., Antonakos, B., Chen, C. H., Chen, Z., Cooke, V. G., Dobson, J. R., Deng, Z., Feng, F., Firestone, B., Fodor, M., Fridrich, C., Gao, H., Grunenfelder, D., Hao, H., . . . Fortin, P. D. (2016). Allosteric inhibition of SHP2 phosphatase inhibits cancers driven by receptor tyrosine kinases. Nature, 535(7610), 148–152. https://doi.org/10.1038/nature18621 

Darian, E., Guvench, O., Yu, B., Qu, C. K., & MacKerell, A. D. (2011). Structural mechanism associated with domain opening in gain‐of‐function mutations in SHP2 phosphatase. Proteins: Structure, Function, and Bioinformatics, 79(5), 1573–1588. https://doi.org/10.1002/prot.22984

Dong, L., Han, D. W., Meng, X., Xu, M., Zheng, C., & Qin, X. (2021). Activating mutation of SHP2 establishes a tumorigenic phonotype through Cell-Autonomous and Non-Cell-Autonomous mechanisms. Frontiers in Cell and Developmental Biology, 9. https://doi.org/10.3389/fcell.2021.630712

Neel, B. G., Gu, H., & Pao, L. (2003). The ‘Shp’ing news: SH2 domain-containing tyrosine phosphatases in cell signaling. Trends in Biochemical Sciences, 28(6), 284–293. https://doi.org/10.1016/s0968-0004(03)00091-4

Nichols, R. J., Haderk, F., Stahlhut, C., Schulze, C. J., Hemmati, G., Wildes, D., Tzitzilonis, C., Mordec, K., Marquez, A., Romero, J. M., Hsieh, T., Zaman, A., Olivas, V., McCoach, C. E., Blakely, C. M., Wang, Z., Kiss, G., Koltun, E. S., Gill, A. L., . . . Bivona, T. G. (2018). RAS nucleotide cycling underlies the SHP2 phosphatase dependence of mutant BRAF-, NF1- and RAS-driven cancers. Nature Cell Biology, 20(9), 1064–1073. https://doi.org/10.1038/s41556-018-0169-1 

Shen, D., Chen, W., Zhu, J., Wu, G., Shen, R., Xi, M., & Sun, H. (2020). Therapeutic potential of targeting SHP2 in human developmental disorders and cancers. European Journal of Medicinal Chemistry, 190, 112117. https://doi.org/10.1016/j.ejmech.2020.112117

Song, Y., Zhao, M., Zhang, H., & Yu, B. (2022). Double-edged roles of protein tyrosine phosphatase SHP2 in cancer and its inhibitors in clinical trials. Pharmacology & Therapeutics, 230, 107966. https://doi.org/10.1016/j.pharmthera.2021.107966

Taylor, A. M., Williams, B. R., Giordanetto, F., Kelley, E. H., Lescarbeau, A., Shortsleeves, K., Tang, Y., Walters, W. P., Arrazate, A., Bowman, C. M., Brophy, E., Chan, E., Deshmukh, G., Greisman, J. B., Hunsaker, T., Kipp, D. R., Lopez-Larrocha, P. S., Maddalo, D., Martin, I., . . . Willmore, L. (2023). Identification of GDC-1971 (RLY-1971), a SHP2 inhibitor designed for the treatment of solid tumors. Journal of Medicinal Chemistry, 66(19), 13384–13399. https://doi.org/10.1021/acs.jmedchem.3c00483

Wang, Q., Zhao, W., Fu, X., & Zheng, Q. (2020). Exploring the allosteric mechanism of SRC Homology-2 Domain-Containing protein Tyrosine phosphatase 2 (SHP2) by molecular dynamics simulations. Frontiers in Chemistry, 8. https://doi.org/10.3389/fchem.2020.597495 

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