Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2024 Mar 5:15:1340726.
doi: 10.3389/fimmu.2024.1340726. eCollection 2024.

Tyrosine phosphatase PTPN11/ SHP2 in solid tumors - bull's eye for targeted therapy?

Xun Chen  1   2 , Steffen Johannes Keller  1 , Philipp Hafner  1 , Asma Y Alrawashdeh  1 , Thomas Yul Avery  1 , Johana Norona  1   3 , Jinxue Zhou  2 , Dietrich Alexander Ruess  1   3
Affiliations
Review

Tyrosine phosphatase PTPN11/ SHP2 in solid tumors - bull's eye for targeted therapy?

Xun Chen et al. Front Immunol. .

Abstract

Encoded by PTPN11, the Src-homology 2 domain-containing phosphatase 2 (SHP2) integrates signals from various membrane-bound receptors such as receptor tyrosine kinases (RTKs), cytokine and integrin receptors and thereby promotes cell survival and proliferation. Activating mutations in the PTPN11 gene may trigger signaling pathways leading to the development of hematological malignancies, but are rarely found in solid tumors. Yet, aberrant SHP2 expression or activation has implications in the development, progression and metastasis of many solid tumor entities. SHP2 is involved in multiple signaling cascades, including the RAS-RAF-MEK-ERK-, PI3K-AKT-, JAK-STAT- and PD-L1/PD-1- pathways. Although not mutated, activation or functional requirement of SHP2 appears to play a relevant and context-dependent dichotomous role. This mostly tumor-promoting and infrequently tumor-suppressive role exists in many cancers such as gastrointestinal tumors, pancreatic, liver and lung cancer, gynecological entities, head and neck cancers, prostate cancer, glioblastoma and melanoma. Recent studies have identified SHP2 as a potential biomarker for the prognosis of some solid tumors. Based on promising preclinical work and the advent of orally available allosteric SHP2-inhibitors early clinical trials are currently investigating SHP2-directed approaches in various solid tumors, either as a single agent or in combination regimes. We here provide a brief overview of the molecular functions of SHP2 and collate current knowledge with regard to the significance of SHP2 expression and function in different solid tumor entities, including cells in their microenvironment, immune escape and therapy resistance. In the context of the present landscape of clinical trials with allosteric SHP2-inhibitors we discuss the multitude of opportunities but also limitations of a strategy targeting this non-receptor protein tyrosine phosphatase for treatment of solid tumors.

Keywords: SHP2; immune microenvironment; signaling pathway; solid tumor; therapy resistance; tumor microenvironment.

PubMed Disclaimer

Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Molecular structure of SHP2 and mechanism of activation and inhibition: (A) SHP2 functional domains. (B) SHP2 in the inhibited and activated state from different manners.
Figure 2
Figure 2
SHP2 signaling pathways: SHP2-dependent signaling in both developing and established cancer cells is illustrated, with arrows denoting positive regulators and T-bars indicating negative regulators. Functioning as a convergence node, SHP2 exhibits diverse roles in cell survival-related signaling pathways. It not only positively influences the RAS-RAF-MEK-ERK pathway but also modulates the PI3K-AKT and JAK-STAT pathways, either enhancing or antagonizing based on extracellular stimuli and the cellular environment. Additionally, SHP2 is involved in Wnt/β-catenin and NF-κB pathways. Nuclear localization of SHP2 has been observed in various contexts, and in the Hippo signaling pathway, YAP and TAZ act as the rheostat for nuclear SHP2 function.
Figure 3
Figure 3
The role of SHP2 in different solid tumor entities. SHP2 primarily serves as a tumor promoter in most solid entities. However, its role in liver and colorectal cancer is dual, encompassing both promoting and suppressing functions. The involvement of SHP2 in prostate cancer remains controversial.
Figure 4
Figure 4
Immune cell-specific roles of SHP2. (A) SHP2 in T lymphocytes. SHP2 is recruited by various immunosuppressive receptors like PD-1, CTLA-4, BTLA, TIGIT, etc. The immunosuppressive effects of SHP2 via PD-1 involve (1): direct inhibition of the PI3K-AKT signaling pathway (2); dephosphorylation of ZAP70, indirect inhibition of PI3K-AKT and RAS-ERK pathways (3); dephosphorylation of CD28 to indirectly inhibit the PI3K-AKT pathway (4); For CTLA-4, cytoplasmic SHP2 antagonizes CD28 positive signals, playing a tumor-promoting role (5); PD-1 disrupts CD226 activation through distinct mechanisms when converging with TIGIT (6); SHP2 dephosphorylates ITK downstream of PD-1, inhibiting T cell function. Downstream signaling of SHP2 recruited by BTLA remains unclear. (B) SHP2 in myeloid cells/macrophages. SHP2 promotes tumor growth via TAMs through (1): binding to CSF-1-induced signaling complexes, enhancing macrophage proliferation and M2 polarization under CSF-1 stimulation (2); recruiting SIRPα or Siglec-10 receptors to reduce phagocytosis upon CD47 or CD24 stimulation (3); promoting macrophage proliferation via a macrophage/CXCL9-Th1 cell/IFN-γ feedback loop (4); dephosphorylating STAT downstream of IL-10 signaling, inhibiting anti-inflammatory factors, and exacerbating colitis-related colon cancer (5); attenuating GM-CSF-mediated phosphorylation of HOXA10 and IRF8.
See this image and copyright information in PMC

Similar articles

See all similar articles

References

    1. Vaghari-Tabari M, Ferns GA, Qujeq D, Andevari AN, Sabahi Z, Moein S. Signaling, metabolism, and cancer: An important relationship for therapeutic intervention. J Cell Physiol. (2021) 236:5512–32. doi: 10.1002/jcp.30276 - DOI - PubMed
    1. Zhang J, Zhang F, Niu R. Functions of shp2 in cancer. J Cell Mol Med. (2015) 19:2075–83. doi: 10.1111/jcmm.12618 - DOI - PMC - PubMed
    1. Yu B, Liu W, Yu WM, Loh ML, Alter S, Guvench O, et al. . Targeting protein tyrosine phosphatase SHP2 for the treatment of PTPN11-associated Malignancies. Mol Cancer Ther. (2013) 12:1738–48. doi: 10.1158/1535-7163.MCT-13-0049-T - DOI - PMC - PubMed
    1. Pandey R, Saxena M, Kapur R. Role of SHP2 in hematopoiesis and leukemogenesis. Curr Opin Hematol. (2017) 24:307–13. doi: 10.1097/MOH.0000000000000345 - DOI - PMC - PubMed
    1. Zhou J, Guo H, Zhang Y, Liu H, Dou Q. Prognostic significance of SHP2 (PTPN11) expression in solid tumors: A meta-analysis. PloS One. (2022) 17:e0262931. doi: 10.1371/journal.pone.0262931 - DOI - PMC - PubMed

Publication types

Substances

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. DR is supported by the German Research Foundation (DFG), CRC1479 (Project-ID:441891347) and by the German Cancer Aid (grant number 70113697). XC is supported by the China Scholarship Council (grant number 202208080226).
-