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Abstract
Gain-of-function mutation of SHP2 is a central regulator in tumorigenesis and cancer progression through cell-autonomous mechanisms. Activating mutation of SHP2 in microenvironment was identified to promote cancerous transformation of hematopoietic stem cell in non-autonomous mechanisms. It is interesting to see whether therapies directed against SHP2 in tumor or microenvironmental cells augment antitumor efficacy. In this review, we summarized different types of gain-of-function SHP2 mutations from a human disease. In general, gain-of-function mutations destroy the auto-inhibition state from wild-type SHP2, leading to consistency activation of SHP2. We illustrated how somatic or germline mutation of SHP2 plays an oncogenic role in tumorigenesis, stemness maintenance, invasion, etc. Moreover, the small-molecule SHP2 inhibitors are considered as a potential strategy for enhancing the efficacy of antitumor immunotherapy and chemotherapy. We also discussed the interconnection between phase separation and activating mutation of SHP2 in drug resistance of antitumor therapy.
Highlights
Protein tyrosine phosphatases (PTPs) are widely expressed in most tissues
SHP2 serves as a pivotal hub to connect multiple oncogenic signaling pathways, such as PI3K/Akt, Ras/Raf/mitogen-activated protein kinase (MAPK), and programmed cell death 1 (PD-1)/PD-L1 pathways
Oncogenic SHP2 is regarded as a potential cancer treatment target
Summary
Protein tyrosine phosphatases (PTPs) are widely expressed in most tissues. They play a regulatory role in various cell signaling events, such as mitogenic activation, metabolic control, transcription regulation, and cell migration. Treatment of NSCLC by tyrosine kinase inhibitor (TKI) failed because SHP2 induces the stemness of KRAS-mutant NSCLCs. The inhibition of SHP2 attenuates the enhanced stemness (Jiang et al, 2019), suggesting the important role of tumor cell-autonomous SHP2 in stemness maintenance of CSCs. Other studies revealed that SHP2 catalytic activity is required for proliferation and tumorigenic transformation of GSCs (Roccograndi et al, 2017).
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