2018年10月30日 · Here, we dissect the energy landscape of wild-type SHP2 and the oncogenic mutation E76K. NMR spectroscopy and X-ray crystallography reveal that wild-type SHP2 exchanges between closed, inactive...

Somatic mutation E76K in SHP2 is the most commonly identified mutation found in up to 35% of patients with JMML. To investigate the effect of gain-of-function mutation-E76K on SHP2 activity, molecular dynamic simulations on the wild-type SHP2 (SHP2-WT) system and the mutated E76K (SHP2-E76K) system were performed.

2023年12月21日 · By molecular dynamics simulations and accurate explicit-solvent SAXS curve predictions, we present the heterogeneous atomistic ensemble of constitutively active SHP2 E76K in solution,...

Here, we uncover a common liquid-liquid phase separation (LLPS) behavior shared by these disease-associated SHP2 mutants. SHP2 LLPS is mediated by the conserved well-folded PTP domain through multivalent electrostatic interactions and regulated by an intrinsic autoinhibitory mechanism through conformational changes.

2007年12月12日 · Gain-of-function Shp2 mutants such as Shp2 E76K are associated with myeloid leukemias. We found that Shp2 E76K could transform cytokine-dependent human TF-1 myeloid cells into cytokine-independence and further characterized the Shp2 E76K -induced cell survival mechanism in this study.

2023年2月1日 · The oncogenic mutation E76K in SHP2 releases the enzyme from an autoinhibited, closed conformation into an active, open conformation. Here, we investigated the conformational dynamics of SHP2 and the effect of the E76K mutation on its conformational ensemble via extensive molecular dynamics (MD) and metadynamics (MetaD) simulations.

The E76K GOF mutation is the most common and active SHP2 mutation; however, the pathogenic effects and function of this mutation in CRC tumor progression have not been well characterized. The Wnt/β-catenin (CTNNB1) signaling pathway is crucial for CRC, and excessive activation of this pathway has been observed in several tumors.

2018年1月11日 · The E76K GOF mutation is the most common and active SHP2 mutation; however, the pathogenic effects and function of this mutation in CRC tumor progression have not been well characterized. The Wnt/β-catenin (CTNNB1) signaling pathway is crucial for CRC, and excessive activation of this pathway has been observed in several tumors.

2024年6月1日 · To identify phosphatase activators of SHP2 that could maintain its open conformation, we performed a two-step screening assay using SHP2-E76K (1–525), an active open-state mutant of SHP2. Protein thermal shift technology was used in primary screening to obtain compounds that stabilized SHP2-E76K.

Somatic mutation E76K in SHP2 is the most commonly identified mutation found in up to 35% of patients with JMML. To investigate the effect of gain-of-function mutation-E76K on SHP2 activity, molecular dynamic simulations on the wild-type SHP2 (SHP2-WT) system and the mutated E76K (SHP2-E76K) system were performed.