Cancer-associated mutations in the p85α N-terminal SH2 domain activate a spectrum of receptor tyrosine kinases

Li, Xinran; Lau, Amy Yuet Ting; Ng, Angel S N; Aldehaiman, Abdullah; Zhou, Yuan; Ng, Patrick Kwok Shing; Arold, Stefan T.; Cheung, Lydia W.T.

doi:10.1073/pnas.2101751118

Cited by 11 publications

(5 citation statements)

References 45 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Even though X582 splice alteration has been previously identified and considered as pathogenic [144], its exact functional consequences have not been elucidated yet. Finally, the nSH2 domainlocated G376R substitution acts in the same way as the previously discussed E545 and E542 substitutions of the p110alpha protein, thus attenuating the inhibitory interaction between the regulatory and the catalytic subunit of the PI3K complex and enhancing the PI3K/AKT signaling [145,146].…”

Section: The Pi3k/akt Pathwaymentioning

confidence: 79%

Targeting Oncogenic Pathways in the Era of Personalized Oncology: A Systemic Analysis Reveals Highly Mutated Signaling Pathways in Cancer Patients and Potential Therapeutic Targets

Karagiannakos

Adamaki

Tsintarakis

et al. 2022

Cancers

View full text Add to dashboard Cite

Cancer is the second leading cause of death globally. One of the main hallmarks in cancer is the functional deregulation of crucial molecular pathways via driver genetic events that lead to abnormal gene expression, giving cells a selective growth advantage. Driver events are defined as mutations, fusions and copy number alterations that are causally implicated in oncogenesis. Molecular analysis on tissues that have originated from a wide range of anatomical areas has shown that mutations in different members of several pathways are implicated in different cancer types. In recent decades, significant efforts have been made to incorporate this knowledge into daily medical practice, providing substantial insight towards clinical diagnosis and personalized therapies. However, since there is still a strong need for more effective drug development, a deep understanding of the involved signaling mechanisms and the interconnections between these pathways is highly anticipated. Here, we perform a systemic analysis on cancer patients included in the Pan-Cancer Atlas project, with the aim to select the ten most highly mutated signaling pathways (p53, RTK-RAS, lipids metabolism, PI-3-Kinase/Akt, ubiquitination, b-catenin/Wnt, Notch, cell cycle, homology directed repair (HDR) and splicing) and to provide a detailed description of each pathway, along with the corresponding therapeutic applications currently being developed or applied. The ultimate scope is to review the current knowledge on highly mutated pathways and to address the attractive perspectives arising from ongoing experimental studies for the clinical implementation of personalized medicine.

show abstract

Section: The Pi3k/akt Pathwaymentioning

confidence: 79%

Targeting Oncogenic Pathways in the Era of Personalized Oncology: A Systemic Analysis Reveals Highly Mutated Signaling Pathways in Cancer Patients and Potential Therapeutic Targets

Karagiannakos

Adamaki

Tsintarakis

et al. 2022

Cancers

View full text Add to dashboard Cite

show abstract

“…Three domains: EGF-like domain, Src homology 2 (SH2) domain and SH2 domain superfamily were significantly enriched in this study. p85α SH2 domain mutation is involved in activating a spectrum of receptor tyrosine kinases, including EGFR [37].…”

Section: Discussionmentioning

confidence: 99%

Potential Inhibitors of EGFR Tyrosine Kinase from <em>Scutellaria baicalensis</em>: A Cheminformatics and Molecular Docking Studies

Yusuf¹,

Adegboyega²,

Yakubu³

et al. 2022

Preprint

View full text Add to dashboard Cite

Epidermal Growth Factor Receptor (EGFR) tyrosine kinase is a cell surface receptor whose overexpression has been associated with different types of cancers including brain cancer (glioblastoma multiforme). The ability of the extract of Scutellaria baicalensis to inhibit the proliferation of malignant glioma cells have been reported. Thus, in this study we report the identification of 307 bioactive constituents responsible for the anti-glioblastoma multiforme effect from S. baicalensis using in silico studies such as molecular docking, binding free energy calculations, pharmacophore modelling, induced-fit docking, gene enrichment analysis, molecular dynamic simulations and AD-MET predictions. A total of 307 chemical constituents of S. baicalensis were screened and the top 10 scoring compounds indicated different binding affinities ranging from -9.010 to -6.427 kcal/mol towards the EGFR tyrosine kinase; Ganhuangenin, 5,7,2',5'-tetrahydroxyflavone, (2R)-2-(2,6-dihydroxyphenyl)-3,4-dihydro-2H-chromene-5,7-diol, and tenaxin I possess higher binding affinities (-9.010 to -8.649 kcal/mol) compared to the standard ligand, erlotinib having -8.539 kcal/mol. The

show abstract

“…ligands containing phosphotyrosine motifs) can activate p110α by disrupting the inhibitory SH2:p110α interactions. This mechanism also explains the disease-associated effects of many mutations in these domains (Carpenter et al, 1993;Li et al, 2021). However, this model cannot explain how ligands of the other p85α regions activate p110α.…”

Section: Introductionmentioning

confidence: 98%

Functional selection in SH3-mediated activation of the PI3 kinase

Aljedani,

Aldehaiman,

Sandholu

et al. 2024

Preprint

Self Cite

View full text Add to dashboard Cite

The phosphoinositide-3 kinase (PI3K), a heterodimeric enzyme, plays a pivotal role in cellular metabolism and survival. Its deregulation is associated with major human diseases, particularly cancer. The p85 regulatory subunit of PI3K binds to the catalytic p110 subunit via its C-terminal domains, stabilizing it in an inhibited state. Certain Src homology 3 (SH3) domains can activate p110 by binding to the proline-rich (PR) 1 motif located at the N-terminus of p85. However, the mechanism by which this N-terminal interaction activates the C-terminally bound p110 remains elusive. Moreover, the intrinsically poor ligand selectivity of SH3 domains raises the question of how they can control PI3K. Combining structural, biophysical, and functional methods, we demonstrate that the answers to both these unknown issues are linked: PI3K-activating SH3 domains engage in additional tertiary interactions with the C-terminal domains of p85, thereby relieving their inhibition of p110. SH3 domains lacking these tertiary interactions may still bind to p85 but cannot activate PI3K. Thus, p85 uses a functional selection mechanism that precludes nonspecific activation rather than nonspecific binding. This separation of binding and activation may provide a general mechanism for how biological activities can be controlled by promiscuous protein-protein interaction domains.

show abstract

Cancer-associated mutations in the p85α N-terminal SH2 domain activate a spectrum of receptor tyrosine kinases

Cited by 11 publications

References 45 publications

Targeting Oncogenic Pathways in the Era of Personalized Oncology: A Systemic Analysis Reveals Highly Mutated Signaling Pathways in Cancer Patients and Potential Therapeutic Targets

Targeting Oncogenic Pathways in the Era of Personalized Oncology: A Systemic Analysis Reveals Highly Mutated Signaling Pathways in Cancer Patients and Potential Therapeutic Targets

Potential Inhibitors of EGFR Tyrosine Kinase from <em>Scutellaria baicalensis</em>: A Cheminformatics and Molecular Docking Studies

Functional selection in SH3-mediated activation of the PI3 kinase

Contact Info

Product

Resources

About