SHP2 clinical phenotype, cancer, or RASopathies, can be predicted by mutant conformational propensities

Liu, Yonglan; Zhang, Wengang; Jang, Hyunbum; Nussinov, Ruth

doi:10.1007/s00018-023-05052-8

Cited by 6 publications

(5 citation statements)

References 122 publications

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“…Pathologically, SHP2 mutants with enhanced activity can disturb this balance. Hyperactive SHP2 driven by mutations (e.g., E76K, D62Y, and D62 V) leads to an excessive presence of Y992 over pY992 on EGFR, reducing RASA1’s accumulation at the membrane. , It is still not clear which phosphatase dephosphorylates pY1101. Earlier studies implicated T cell protein tyrosine phosphatase (TC-PTP) in negatively regulating EGFR signaling by dephosphorylating multiple tyrosine residues on EGFR, including pY1101 …”

Section: Discussionmentioning

confidence: 99%

“…SHP2 is a positive regulator in the RTK-dependent Ras signaling pathway. It stands out as a major cancer drug target. ,,,− There are two types of SHP2 inhibitors: active-site (type I) inhibitors binding the activated, open SHP2, ,,, and allosteric (type II) inhibitors that bind the closed state. Allosteric inhibitors are effective when targeting wild-type SHP2, but they may exhibit reduced potency in the presence of a strong activating mutation (e.g., E76K) at the interface between the nSH2 and PTP domains, ,, making active-site inhibitors a more desirable option.…”

Section: Discussionmentioning

confidence: 99%

“…SHP2 has three sequential domains: the nSH2, cSH2, and PTP domains (Figure S2a). , Autoinhibited SHP2 adopts a closed conformation with nSH2 tightly bound to the catalytic cleft of the PTP domain . SHP2 activation involves nSH2 release by its (and cSH2) binding to pY sites in RTKs or adapter proteins, exposing the active site (Figure S2b).…”

Section: Introductionmentioning

confidence: 99%

“…SHP2 activation involves nSH2 release by its (and cSH2) binding to pY sites in RTKs or adapter proteins, exposing the active site (Figure S2b). Gab1 is a well-known activator of SHP2. ,, Mutations at the nSH2-PTP interface, such as the SHP2 E76K variant, promote an open conformation with an exposed active site. , Upon activation, SHP2 dephosphorylates EGFR’s pY site. When phosphorylated, it is recognized by RASA1.…”

Section: Introductionmentioning

confidence: 99%

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SHP2–EGFR States in Dephosphorylation Can Inform Selective SHP2 Inhibitors, Dampening RasGAP Action

Liu,

Jang,

Nussinov

2024

J. Phys. Chem. B

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SHP2 is a positive regulator of the EGFR-dependent Ras/MAPK pathway. It dephosphorylates a regulatory phosphorylation site in EGFR that serves as the binding site to RasGAP (RASA1 or p120RasGAP). RASA1 is activated by binding to the EGFR phosphate group. Active RASA1 deactivates Ras by hydrolyzing Ras-bound GTP to GDP. Thus, SHP2 dephosphorylation of EGFR effectively prevents RASA1-mediated deactivation of Ras, thereby stimulating proliferation. Despite knowledge of this vital regulation in cell life, mechanistic in-depth structural understanding of the involvement of SHP2, EGFR, and RASA1 in the Ras/MAPK pathway has largely remained elusive. Here we elucidate the interactions, the factors influencing EGFR’s recruitment of RASA1, and SHP2’s recognition of the substrate site in EGFR. We reveal that RASA1 specifically interacts with the DEpY992LIP motif in EGFR featuring a proline residue at the +3 position C-terminal to pY primarily through its nSH2 domain. This interaction is strengthened by the robust attraction of two acidic residues, E991 and D990, of EGFR to two basic residues in the BC-loop near the pY-binding pocket of RASA1’s nSH2. In the stable precatalytic state of SHP2 with EGFR (DADEpY992LIPQ), the E-loop of SHP2’s active site favors the interaction with the (−2)-position D990 and (−4)-position D988 N-terminal to pY992 in EGFR, while the pY-loop constrains the (+4)-position Q996 C-terminal to pY992. These specific interactions not only provide a structural basis for identifying negative regulatory sites in other RTKs but can inform selective, high-affinity active-site SHP2 inhibitors tailored for SHP2 mutants.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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SHP2–EGFR States in Dephosphorylation Can Inform Selective SHP2 Inhibitors, Dampening RasGAP Action

Liu,

Jang,

Nussinov

2024

J. Phys. Chem. B

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“…As to why the epidemiological connection, we reason that one possible clue is the established cancer statistics: A single mutation is insufficient to elicit cancer, although exactly how many mutations are required for cancer to emerge has been a debated question ( Tomlinson et al, 2002 ; Tomasetti et al, 2015 ; Martincorena et al, 2017 ; Liu et al, 2023 ). Going back to the question we posed above, why then individuals with neurodevelopmental disorders, such as autism and schizophrenia, may face higher chances of cancer emerging throughout their lifetime?…”

Section: Introduction: Background and Premisementioning

confidence: 99%

Review: Cancer and neurodevelopmental disorders: multi-scale reasoning and computational guide

Nussinov,

Yavuz,

Demirel

et al. 2024

Front. Cell Dev. Biol.

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The connection and causality between cancer and neurodevelopmental disorders have been puzzling. How can the same cellular pathways, proteins, and mutations lead to pathologies with vastly different clinical presentations? And why do individuals with neurodevelopmental disorders, such as autism and schizophrenia, face higher chances of cancer emerging throughout their lifetime? Our broad review emphasizes the multi-scale aspect of this type of reasoning. As these examples demonstrate, rather than focusing on a specific organ system or disease, we aim at the new understanding that can be gained. Within this framework, our review calls attention to computational strategies which can be powerful in discovering connections, causalities, predicting clinical outcomes, and are vital for drug discovery. Thus, rather than centering on the clinical features, we draw on the rapidly increasing data on the molecular level, including mutations, isoforms, three-dimensional structures, and expression levels of the respective disease-associated genes. Their integrated analysis, together with chromatin states, can delineate how, despite being connected, neurodevelopmental disorders and cancer differ, and how the same mutations can lead to different clinical symptoms. Here, we seek to uncover the emerging connection between cancer, including pediatric tumors, and neurodevelopmental disorders, and the tantalizing questions that this connection raises.

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Single cell spatial biology over developmental time can decipher pediatric brain pathologies

Nussinov,

Yavuz,

Jang

2024

Neurobiology of Disease

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SHP2 clinical phenotype, cancer, or RASopathies, can be predicted by mutant conformational propensities

Cited by 6 publications

References 122 publications

SHP2–EGFR States in Dephosphorylation Can Inform Selective SHP2 Inhibitors, Dampening RasGAP Action

SHP2–EGFR States in Dephosphorylation Can Inform Selective SHP2 Inhibitors, Dampening RasGAP Action

Review: Cancer and neurodevelopmental disorders: multi-scale reasoning and computational guide

Single cell spatial biology over developmental time can decipher pediatric brain pathologies

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