Phase Separation of Disease-Associated SHP2 Mutants Underlies MAPK Hyperactivation

Zhu, Guangya; Xie, Jingjing; Kong, Wenna; Xie, Jingfei; Li, Yichen; Du, Lin; Zheng, Qiangang; Sun, Lin; Guan, Mingzhi; Li, Huan; Zhu, Tianxin; He, Hao; Liu, Zhenying; Xia, Xi; Chen, Kan; Tao, Youqi; Shen, Hong C.; Li, Dan; Wang, Siying; Yu, Yongguo; Yu, Zhihong; Zhang, Zhong-Yin; Liu, Cong; Zhu, Jidong

doi:10.1016/j.cell.2020.09.002

Cited by 141 publications

(141 citation statements)

References 51 publications

(77 reference statements)

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“…Many of the proteins involved in cancer-associated signaling pathways have been shown to form condensates, thus regulating output of the pathway (Case et al, 2019b;Chong and Forman-Kay, 2016;Su et al, 2016). RAS activation occurs when ligand-bound membrane receptors recruit and modify adaptor proteins, and these adaptor proteins form condensates at the cell membrane that compartmentalize proteins, increasing their ''dwell time'' and RAS activity (Huang et al, 2019;Zhu et al, 2020). These same adaptor protein condensates also accelerate the rate of actin polymerization (Case et al, 2019a).…”

Section: Revisiting Mechanisms In Common Oncogenic Eventsmentioning

confidence: 99%

Biomolecular Condensates and Cancer

2021

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Section: Revisiting Mechanisms In Common Oncogenic Eventsmentioning

confidence: 99%

Biomolecular Condensates and Cancer

2021

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“…Recently, hyperactivation of SHP2 through the formation of LLPS has been elucidated ( Zhu et al, 2020 ). Both GOF and LOF disease-associated SHP2 variants promote LLPS to increase the catalytic activity of mutant and wild-type SHP2, leading to MAPK hyperactivation.…”

Section: Conclusion and Discussionmentioning

confidence: 99%

“…A recent study reported that multivalent electrostatic interaction among the PTP domains leads to liquid–liquid phase separation (LLPS) of mutated SHP2. It recruits wild-type SHP2 and hyperactivates the phosphatase catalytic activity of SHP2, which further leads to hyperactivation of mitogen-activated protein kinase (MAPK) signaling pathway ( Zhu et al, 2020 ). It also reported that SHP2 mutants in LEOPARD syndrome induce robust phase transition to liquid-like droplets in cells, which recruit and activate wild-type SHP2 to promote extracellular signal-regulated kinase1/2 (Erk1/2) activation ( Zhu et al, 2020 ).…”

Section: The Structural Conformation Changes and Functional Regulatiomentioning

confidence: 99%

“…It recruits wild-type SHP2 and hyperactivates the phosphatase catalytic activity of SHP2, which further leads to hyperactivation of mitogen-activated protein kinase (MAPK) signaling pathway ( Zhu et al, 2020 ). It also reported that SHP2 mutants in LEOPARD syndrome induce robust phase transition to liquid-like droplets in cells, which recruit and activate wild-type SHP2 to promote extracellular signal-regulated kinase1/2 (Erk1/2) activation ( Zhu et al, 2020 ). It suggests that disease-associated SHP2 mutations promote GOF LLPS and consequently lead to overactivation of wild-type SHP2.…”

Section: The Structural Conformation Changes and Functional Regulatiomentioning

confidence: 99%

“…A recent study demonstrated that mutated SHP2-mediated LLPS formation is inhibited by SHP2 allosteric inhibitors, which prevent SHP2 from releasing the self-inhibition status. Therefore, the application of SHP2 inhibitors is a promising therapeutic strategy to treat SHP2-involved developmental disorders and tumors ( Zhu et al, 2020 ).…”

Section: Shp2 Inhibition Is a Promising Antitumor Strategymentioning

confidence: 99%

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Activating Mutation of SHP2 Establishes a Tumorigenic Phonotype Through Cell-Autonomous and Non-Cell-Autonomous Mechanisms

Dong

Han

Meng

et al. 2021

Front. Cell Dev. Biol.

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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.

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Contribution of Somatic Ras/Raf/Mitogen-Activated Protein Kinase Variants in the Hippocampus in Drug-Resistant Mesial Temporal Lobe Epilepsy

et al. 2023

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ImportanceMesial temporal lobe epilepsy (MTLE) is the most common focal epilepsy subtype and is often refractory to antiseizure medications. While most patients with MTLE do not have pathogenic germline genetic variants, the contribution of postzygotic (ie, somatic) variants in the brain is unknown.ObjectiveTo test the association between pathogenic somatic variants in the hippocampus and MTLE.Design, Setting, and ParticipantsThis case-control genetic association study analyzed the DNA derived from hippocampal tissue of neurosurgically treated patients with MTLE and age-matched and sex-matched neurotypical controls. Participants treated at level 4 epilepsy centers were enrolled from 1988 through 2019, and clinical data were collected retrospectively. Whole-exome and gene-panel sequencing (each genomic region sequenced more than 500 times on average) were used to identify candidate pathogenic somatic variants. A subset of novel variants was functionally evaluated using cellular and molecular assays. Patients with nonlesional and lesional (mesial temporal sclerosis, focal cortical dysplasia, and low-grade epilepsy–associated tumors) drug-resistant MTLE who underwent anterior medial temporal lobectomy were eligible. All patients with available frozen tissue and appropriate consents were included. Control brain tissue was obtained from neurotypical donors at brain banks. Data were analyzed from June 2020 to August 2022.ExposuresDrug-resistant MTLE.Main Outcomes and MeasuresPresence and abundance of pathogenic somatic variants in the hippocampus vs the unaffected temporal neocortex.ResultsOf 105 included patients with MTLE, 53 (50.5%) were female, and the median (IQR) age was 32 (26-44) years; of 30 neurotypical controls, 11 (36.7%) were female, and the median (IQR) age was 37 (18-53) years. Eleven pathogenic somatic variants enriched in the hippocampus relative to the unaffected temporal neocortex (median [IQR] variant allele frequency, 1.92 [1.5-2.7] vs 0.3 [0-0.9]; P = .01) were detected in patients with MTLE but not in controls. Ten of these variants were in PTPN11, SOS1, KRAS, BRAF, and NF1, all predicted to constitutively activate Ras/Raf/mitogen-activated protein kinase (MAPK) signaling. Immunohistochemical studies of variant-positive hippocampal tissue demonstrated increased Erk1/2 phosphorylation, indicative of Ras/Raf/MAPK activation, predominantly in glial cells. Molecular assays showed abnormal liquid-liquid phase separation for the PTPN11 variants as a possible dominant gain-of-function mechanism.Conclusions and RelevanceHippocampal somatic variants, particularly those activating Ras/Raf/MAPK signaling, may contribute to the pathogenesis of sporadic, drug-resistant MTLE. These findings may provide a novel genetic mechanism and highlight new therapeutic targets for this common indication for epilepsy surgery.

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Phase Separation of Disease-Associated SHP2 Mutants Underlies MAPK Hyperactivation

Cited by 141 publications

References 51 publications

Biomolecular Condensates and Cancer

Biomolecular Condensates and Cancer

Activating Mutation of SHP2 Establishes a Tumorigenic Phonotype Through Cell-Autonomous and Non-Cell-Autonomous Mechanisms

Contribution of Somatic Ras/Raf/Mitogen-Activated Protein Kinase Variants in the Hippocampus in Drug-Resistant Mesial Temporal Lobe Epilepsy

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