Crystallographic landscape of SHP2 provides molecular insights for SHP2 targeted drug discovery

Song, Yihui; Yang, Xinyu; Wang, Shu; Zhao, Min

doi:10.1002/med.21890

Cited by 20 publications

(23 citation statements)

References 76 publications

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“…Tumour tissue samples will then help to reliably identify a tumour subtype and possible molecular targets when surgery had failed. Indeed, a variety of targeted therapies were already developed for the gene product of the PTPN11, such as orthosteric inhibition of the SHP2 protein [34].…”

Section: Discussionmentioning

confidence: 99%

Ganglioglioma with adverse clinical outcome and atypical histopathological features were defined by alterations in PTPN11/KRAS/NF1 and other RAS-/MAP-Kinase pathway genes

et al. 2023

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Exome-wide sequencing studies recently described PTPN11 as a novel brain somatic epilepsy gene. In contrast, germline mutations of PTPN11 are known to cause Noonan syndrome, a multisystem disorder characterized by abnormal facial features, developmental delay, and sporadically, also brain tumors. Herein, we performed a deep phenotype-genotype analysis of a comprehensive series of ganglioglioma (GG) with brain somatic alterations of the PTPN11/KRAS/NF1 genes compared to GG with common MAP-Kinase signaling pathway alterations, i.e., BRAFV600E. Seventy-two GG were submitted to whole exome sequencing and genotyping and 84 low grade epilepsy associated tumors (LEAT) to DNA-methylation analysis. In 28 tumours, both analyses were available from the same sample. Clinical data were retrieved from hospital files including disease onset, age at surgery, brain localization, and seizure outcome. A comprehensive histopathology staining panel was available in all cases. We identified eight GG with PTPN11 alterations, copy number variant (CNV) gains of chromosome 12, and the commonality of additional CNV gains in NF1, KRAS, FGFR4 and RHEB, as well as BRAFV600E alterations. Histopathology revealed an atypical glio-neuronal phenotype with subarachnoidal tumor spread and large, pleomorphic, and multinuclear cellular features. Only three out of eight patients with GG and PTPN11/KRAS/NF1 alterations were free of disabling-seizures 2 years after surgery (38% had Engel I). This was remarkably different from our series of GG with only BRAFV600E mutations (85% had Engel I). Unsupervised cluster analysis of DNA methylation arrays separated these tumours from well-established LEAT categories. Our data point to a subgroup of GG with cellular atypia in glial and neuronal cell components, adverse postsurgical outcome, and genetically characterized by complex alterations in PTPN11 and other RAS-/MAP-Kinase and/or mTOR signaling pathways. These findings need prospective validation in clinical practice as they argue for an adaptation of the WHO grading system in developmental, glio-neuronal tumors associated with early onset focal epilepsy.

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Section: Discussionmentioning

confidence: 99%

Ganglioglioma with adverse clinical outcome and atypical histopathological features were defined by alterations in PTPN11/KRAS/NF1 and other RAS-/MAP-Kinase pathway genes

et al. 2023

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“…In addition, the investigation of the correlation between ZBTB9 and KRAS signaling pathway demonstrated that ZBTB9 was evidently associated with MAPK1, NRAS, SHP2, SOS1, and KRAS2 (all play imperative roles in KRAS pathway [38][39][40]), suggesting that the malignant biological behaviors under ZBTB9 upregulation were probably mediating through this pathways. Blocking of ZBTB9 could have the potential value to optimize the efficacy of inhibitors against KRAS signaling pathways [41,42].…”

Section: Discussionmentioning

confidence: 99%

Identification of ZBTB9 as a potential therapeutic target against dysregulation of tumor cells proliferation and a novel biomarker in Liver Hepatocellular Carcinoma

Zhang

et al. 2022

J Transl Med

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Background Zinc finger and bric-a-brac/tramtrack/broad (ZBTB) domain-containing proteins have been reported to be associated with many tumors’ development. However, in tumor initiation and progression, the role of ZBTB9, one of the protein family, and its prognostic value were yet to be elucidated in Liver Hepatocellular Carcinoma (LIHC). Methods We used R software and online bioinformatics analysis tools such as GEPIA2, cBioPortal, TIMER2, Metascape, UALCAN, STRING, TISIDB, and COSMIC to investigate ZBTB9’s characteristics and function in LIHC, including abnormal expression, carcinogenic role, related signaling pathways and prognostic value. Furthermore, cell experiments (such as formation, wound healing, and transwell assays) and analyses based on clinical samples (such as immunohistochemistry (IHC) and promoter methylation analysis) were conducted to verify pivotal conclusions. Results ZBTB9 was overexpressed in LIHC samples compared to adjacent normal tissues. Through the analysis of genomic alteration and promoter hypomethylation, the clinical value and etiology of abnormal expression of ZBTB9 were preliminarily exlpored. Subsequent evidence showed that it could result in tumor progression and poor prognosis via activating cell cycle, DNA repair, MYC, and KRAS-associated signaling pathways as well as rendering immune dysregulation. After the knockdown of ZBTB9, evidently inhibited capacities of tumor cells proliferation and migration were observed. These results together indicated that ZBTB9 could be a promising prognostic biomarker and had the potential value to offer novel therapeutic targets for LIHC treatment. Conclusions ZBTB9 was identified as a novel biomarker to predict the prognosis and tumor progression in LIHC, and a promising therapeutic target to invert tumor development.

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“…Shp2 keeps an auto-inhibited close conformation with intramolecular interaction between the N-SH2 and PTP domain under the basal state. Binding of a phosphotyrosine-containing peptide to the N-SH2 domain results in a conformational change to relieve this auto-inhibition ( Neel et al, 2003 ; Song et al, 2022 ). In our study, we found that α-actinin-4 may either directly or indirectly interact with the Shp2 at FAs.…”

Section: Discussionmentioning

confidence: 99%

α-Actinin-4 recruits Shp2 into focal adhesions to potentiate ROCK2 activation in podocytes

et al. 2022

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Cell–matrix adhesions are mainly provided by integrin-mediated focal adhesions (FAs). We previously found that Shp2 is essential for FA maturation by promoting ROCK2 activation at FAs. In this study, we further delineated the role of α-actinin-4 in the FA recruitment and activation of Shp2. We used the conditional immortalized mouse podocytes to examine the role of α-actinin-4 in the regulation of Shp2 and ROCK2 signaling. After the induction of podocyte differentiation, Shp2 and ROCK2 were strongly activated, concomitant with the formation of matured FAs, stress fibers, and interdigitating intracellular junctions in a ROCK-dependent manner. Gene knockout of α-actinin-4 abolished the Shp2 activation and subsequently reduced matured FAs in podocytes. We also demonstrated that gene knockout of ROCK2 impaired the generation of contractility and interdigitating intercellular junctions. Our results reveal the role of α-actinin-4 in the recruitment of Shp2 at FAs to potentiate ROCK2 activation for the maintenance of cellular contractility and cytoskeletal architecture in the cultured podocytes.

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Crystallographic landscape of SHP2 provides molecular insights for SHP2 targeted drug discovery

Cited by 20 publications

References 76 publications

Ganglioglioma with adverse clinical outcome and atypical histopathological features were defined by alterations in PTPN11/KRAS/NF1 and other RAS-/MAP-Kinase pathway genes

Ganglioglioma with adverse clinical outcome and atypical histopathological features were defined by alterations in PTPN11/KRAS/NF1 and other RAS-/MAP-Kinase pathway genes

Identification of ZBTB9 as a potential therapeutic target against dysregulation of tumor cells proliferation and a novel biomarker in Liver Hepatocellular Carcinoma

α-Actinin-4 recruits Shp2 into focal adhesions to potentiate ROCK2 activation in podocytes

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