ERK2 CD domain mutation from a human cancer cell line enhanced anchorage-independent cell growth and abnormality in Drosophila

Mahalingam, Marthandan; Ramanathan, Arvind; Ida, Hiroyuki; Murugan, Avaniy Apuram Kannan; Yamaguchi, Masamitsu; Tsuchida, Nobuo

doi:10.3892/or_00000096

Cited by 10 publications

(2 citation statements)

References 6 publications

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“…Disturbance of the CD site by either mutant reduced interactions with well-known substrates, e.g., RSK and ELK, which were confirmed by poorer associations detected in vitro. 24,30,35 However, when expressed in cells with or without endogenous ERK2, these substrates were phosphorylated similarly if not more by E-K than by wild-type ERK2. Other CD site binders include the upstream MEK1/2 activators and the DUSP family inactivators.…”

Section: Localization Of Erk2 E-kmentioning

confidence: 95%

“…The longer RSK fragment 689−752 interacts only with wt ERK2 while the shorter RSK fragment 689−738 lacking the KIM does not bind wt or E-K. Binding of RSK by ERK2 in cells was shown by the Tsuchida lab to be reduced by mutation of E-K, and the Garraway lab reported reduced RSK phosphorylation by mutation of either D or E. 24,30 We found that ELK1, which interacts with the CD site, was still activated in cells by E-K and D-N. 35 As important as direct binding is for all of the interaction tests, the fact that these proteins are still activated in cells suggests that other sites of interaction such as the F site or scaffolded complexes overcome loss of CD site interactions. 48,49 A consequence of the solvent-exposed activation loop conformation in the E-K mutant is loss of activation loop contacts with the MAPK insert (Figure 1A).…”

Section: E-k and D-n Influence Erk2 Interactions With Other Binding P...mentioning

confidence: 99%

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ERK2 Mutations Affect Interactions, Localization, and Dimerization

et al. 2023

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The most frequent ERK2 (MAPK1) mutation in cancers, E322K, lies in the common docking (CD) site, which binds short motifs made up of basic and hydrophobic residues present in the activators MEK1 (MAP2K1) and MEK2 (MAP2K2), in dual specificity phosphatases (DUSPs) that inactivate the kinases, and in many of their substrates. Also, part of the CD site, but mutated less often in cancers, is the preceding aspartate (D321N). These mutants were categorized as gain of function in a sensitized melanoma system. In Drosophila developmental assays, we found that the aspartate but not the glutamate mutant caused gain-of-function phenotypes. Here, we catalogued additional properties of these mutants to accrue greater insight into their functions. A modest increase in nuclear retention of E322K was noted. Binding of ERK2 E322K and D321N to a small group of substrates and regulatory proteins was similar, in spite of differences in CD site integrity. Interactions with a second docking site, the F site, which should be more accessible in E322K, were modestly reduced rather than increased. The crystal structure of ERK2 E322K also indicated a disturbed dimer interface, and reduced dimerization was detected by a two-hybrid test; yet, it was detected in dimers in EGF-treated cells, although to a lesser extent than D321N or wt ERK2. These findings indicate a range of small differences in behaviors that may contribute to increased function of E322K in certain cancers.

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Section: Localization Of Erk2 E-kmentioning

confidence: 95%

Section: E-k and D-n Influence Erk2 Interactions With Other Binding P...mentioning

confidence: 99%

ERK2 Mutations Affect Interactions, Localization, and Dimerization

et al. 2023

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Genomic Correlate of Exceptional Erlotinib Response in Head and Neck Squamous Cell Carcinoma

et al. 2015

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IMPORTANCE Randomized clinical trials demonstrate no benefit for epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors in unselected patients with head and neck squamous cell carcinoma (HNSCC). However, a patient with stage IVA HNSCC received 13 days of neoadjuvant erlotinib and experienced a near-complete histologic response. OBJECTIVE To determine a mechanism of exceptional response to erlotinib therapy in HNSCC. DESIGN, SETTING, AND PARTICIPANTS Single patient with locally advanced HNSCC who received erlotinib monotherapy in a window-of-opportunity clinical trial (patients scheduled to undergo primary cancer surgery are treated briefly with an investigational agent). Whole-exome sequencing of pretreatment tumor and germline patient samples was performed at a quaternary care academic medical center, and a candidate somatic variant was experimentally investigated for mediating erlotinib response. INTERVENTION A brief course of erlotinib monotherapy followed by surgical resection. MAIN OUTCOMES AND MEASURES Identification of pretreatment tumor somatic alterations that may contribute to the exceptional response to erlotinib. Hypotheses were formulated regarding enhanced erlotinib response in preclinical models harboring the patient tumor somatic variant MAPK1 E322K following the identification of tumor somatic variants. RESULTS No EGFR alterations were observed in the pretreatment tumor DNA. Paradoxically, the tumor harbored an activating MAPK1 E322K mutation (allelic fraction 0.13), which predicts ERK activation and erlotinib resistance in EGFR-mutant lung cancer. The HNSCC cells with MAPK1 E322K exhibited enhanced EGFR phosphorylation and erlotinib sensitivity compared with wild-type MAPK1 cells. CONCLUSIONS AND RELEVANCE Selective erlotinib use in HNSCC may be informed by precision oncology approaches.

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Targeting mitochondrial metabolism for metastatic cancer therapy

Passaniti

Kim

Polster

et al. 2022

Molecular Carcinogenesis

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Primary tumors evolve metabolic mechanisms favoring glycolysis for adenosine triphosphate (ATP) generation and antioxidant defenses. In contrast, metastatic cells frequently depend on mitochondrial respiration and oxidative phosphorylation (OxPhos). This reliance of metastatic cells on OxPhos can be exploited using drugs that target mitochondrial metabolism. Therefore, therapeutic agents that act via diverse mechanisms, including the activation of signaling pathways that promote the production of reactive oxygen species (ROS) and/or a reduction in antioxidant defenses may elevate oxidative stress and inhibit tumor cell survival. In this review, we will provide (1) a mechanistic analysis of function‐selective extracellular signal‐regulated kinase‐1/2 (ERK1/2) inhibitors that inhibit cancer cells through enhanced ROS, (2) a review of the role of mitochondrial ATP synthase in redox regulation and drug resistance, (3) a rationale for inhibiting ERK signaling and mitochondrial OxPhos toward the therapeutic goal of reducing tumor metastasis and treatment resistance. Recent reports from our laboratories using metastatic melanoma and breast cancer models have shown the preclinical efficacy of novel and rationally designed therapeutic agents that target ERK1/2 signaling and mitochondrial ATP synthase, which modulate ROS events that may prevent or treat metastatic cancer. These findings and those of others suggest that targeting a tumor's metabolic requirements and vulnerabilities may inhibit metastatic pathways and tumor growth. Approaches that exploit the ability of therapeutic agents to alter oxidative balance in tumor cells may be selective for cancer cells and may ultimately have an impact on clinical efficacy and safety. Elucidating the translational potential of metabolic targeting could lead to the discovery of new approaches for treatment of metastatic cancer.

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ERK2 CD domain mutation from a human cancer cell line enhanced anchorage-independent cell growth and abnormality in Drosophila

Cited by 10 publications

References 6 publications

ERK2 Mutations Affect Interactions, Localization, and Dimerization

ERK2 Mutations Affect Interactions, Localization, and Dimerization

Genomic Correlate of Exceptional Erlotinib Response in Head and Neck Squamous Cell Carcinoma

Targeting mitochondrial metabolism for metastatic cancer therapy

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