A cancer mutation promotes EphA4 oligomerization and signaling by altering the conformation of the SAM domain

Light, Taylor P.; Gómez-Soler, Maricel; Wang, Zichen; Karl, Kelly; Zapata-Mercado, Elmer; Gehring, Marina P.; Lechtenberg, Bernhard C.; Pogorelov, Taras V.; Hristova, Kalina; Pasquale, Elena B.

doi:10.1016/j.jbc.2021.100876

Cited by 11 publications

(9 citation statements)

References 94 publications

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“…The juxtamembrane segment and activation loop in the kinase domain control kinase activity through a mechanism involving tyrosine phosphorylation 7 – 9 . Depending on the Eph receptor, the SAM domain can also differentially affect kinase activity 10 – 13 . How the SAM domain affects kinase activity and the potential interplay between the juxtamembrane segment, kinase domain and SAM domain are poorly understood 14 .…”

Section: Introductionmentioning

confidence: 99%

Regulation of the EphA2 receptor intracellular region by phosphomimetic negative charges in the kinase-SAM linker

et al. 2021

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Eph receptor tyrosine kinases play a key role in cell-cell communication. Lack of structural information on the entire multi-domain intracellular region of any Eph receptor has hindered understanding of their signaling mechanisms. Here, we use integrative structural biology to investigate the structure and dynamics of the EphA2 intracellular region. EphA2 promotes cancer malignancy through a poorly understood non-canonical form of signaling involving serine/threonine phosphorylation of the linker connecting its kinase and SAM domains. We show that accumulation of multiple linker negative charges, mimicking phosphorylation, induces cooperative changes in the EphA2 intracellular region from more closed to more extended conformations and perturbs the EphA2 juxtamembrane segment and kinase domain. In cells, linker negative charges promote EphA2 oligomerization. We also identify multiple kinases catalyzing linker phosphorylation. Our findings suggest multiple effects of linker phosphorylation on EphA2 signaling and imply that coordination of different kinases is necessary to promote EphA2 non-canonical signaling.

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Section: Introductionmentioning

confidence: 99%

Regulation of the EphA2 receptor intracellular region by phosphomimetic negative charges in the kinase-SAM linker

et al. 2021

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“…Molecular dynamics was already implemented to study the effect of the melanoma-related mutation L920F in EphA4-Sam, revealing that this mutation might cause a conformational change in EphA4-Sam, thus affecting its oligomerization state [ 68 ]. A recent study analysed the possible outcomes induced by several non-small-cell lung cancer (NSCLC)-related missense mutations on the structures of the ephrinA2 receptor binding domain, EphA3 ligand binding, and kinase domains, and the EphA7, EphB1, and EphB4 kinase domains through MD simulations [ 69 ].…”

Section: Resultsmentioning

confidence: 99%

Cancer-Related Mutations in the Sam Domains of EphA2 Receptor and Ship2 Lipid Phosphatase: A Computational Study

Vincenzi,

Mercurio,

Autiero

et al. 2024

Molecules

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The lipid phosphatase Ship2 interacts with the EphA2 receptor by forming a heterotypic Sam (sterile alpha motif)–Sam complex. Ship2 works as a negative regulator of receptor endocytosis and consequent degradation, and anti-oncogenic effects in cancer cells should be induced by hindering its association with EphA2. Herein, a computational approach is presented to investigate the relationship between Ship2-Sam/EphA2-Sam interaction and cancer onset and further progression. A search was first conducted through the COSMIC (Catalogue of Somatic Mutations in Cancer) database to identify cancer-related missense mutations positioned inside or close to the EphA2–Sam and Ship2–Sam reciprocal binding interfaces. Next, potential differences in the chemical–physical properties of mutant and wild-type Sam domains were evaluated by bioinformatics tools based on analyses of primary sequences. Three-dimensional (3D) structural models of mutated EphA2–Sam and Ship2–Sam domains were built as well and deeply analysed with diverse computational instruments, including molecular dynamics, to classify potentially stabilizing and destabilizing mutations. In the end, the influence of mutations on the EphA2–Sam/Ship2–Sam interaction was studied through docking techniques. This in silico approach contributes to understanding, at the molecular level, the mutation/cancer relationship by predicting if amino acid substitutions could modulate EphA2 receptor endocytosis.

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“…Ephrin receptor A4 (EPHA4) regulates many normal biologic and pathologic processes. Evidence suggests a role of EPHA4 in tumor development and progression [ 36 , 37 ]. Elevated expression of EPHA4 was found in head and neck cancers [ 38 ], although differential outcomes of EphB4-ephrinB2 (its ligand) signaling have been reported in these neoplasms.…”

Section: Discussionmentioning

confidence: 99%

An ErbB Lineage Co-Regulon Harbors Potentially Co-Druggable Targets for Multimodal Precision Therapy in Head and Neck Squamous Cell Carcinoma

Bredel

Kim

Bonner

2022

IJMS

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The ErbB lineage of oncogenic receptor tyrosine kinases is frequently overexpressed in head and neck squamous cell carcinomas. A common co-regulon triggered by the ErbB proteins; involving shared signaling circuitries; may harbor co-druggable targets or response biomarkers for potential future multimodal precision therapy in ErbB-driven head and neck squamous cell carcinoma. We here present a cohort-based; genome-wide analysis of 488 head and neck squamous cell carcinomas curated as part of The Cancer Genome Atlas Project to characterize genes that are significantly positively co-regulated with the four ErbB proteins and those that are shared among all ErbBs denoting a common ErbB co-regulon. Significant positive gene correlations involved hundreds of genes that were co-expressed with the four ErbB family members (q < 0.05). A common; overlapping co-regulon consisted of a core set of 268 genes that were uniformly co-regulated with all four ErbB genes and highly enriched for functions in chromatin organization and histone modifications. This high-priority set of genes contained ten putative antineoplastic drug-gene interactions. The nature and directionality of these ten drug-gene associations was an inhibiting interaction for seven (PIK3CB; PIK3C2B; HDAC4; FRK; PRKCE; EPHA4; and DYRK1A) of them in which the drug decreases the biological activity or expression of the gene target. For three (CHD4; ARID1A; and PBRM1) of the associations; the directionality of the interaction was such that the gene predicted sensitivit y to the drug suggesting utility as potential response biomarkers. Drug-gene interactions that predicted the gene product to be reduced by the drug included a variety of potential targeted molecular agent classes. This unbiased genome-wide analysis identified a target-rich environment for multimodal therapeutic approaches in tumors that are putatively ErbB-driven. The results of this study require preclinical validation before ultimately devising lines of combinatorial treatment strategies for ErbB-dependent head and neck squamous cell carcinomas that incorporate these findings.

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A cancer mutation promotes EphA4 oligomerization and signaling by altering the conformation of the SAM domain

Cited by 11 publications

References 94 publications

Regulation of the EphA2 receptor intracellular region by phosphomimetic negative charges in the kinase-SAM linker

Regulation of the EphA2 receptor intracellular region by phosphomimetic negative charges in the kinase-SAM linker

Cancer-Related Mutations in the Sam Domains of EphA2 Receptor and Ship2 Lipid Phosphatase: A Computational Study

An ErbB Lineage Co-Regulon Harbors Potentially Co-Druggable Targets for Multimodal Precision Therapy in Head and Neck Squamous Cell Carcinoma

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