Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.12.2 (MEK)
 18,161 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The HER-2 oncogene, a member of the erythroblastosis oncogene B (ERBB)-like oncogene family, has been shown to be amplified in many types of cancer, including breast cancer. However, the molecular mechanism of HER-2 overexpression is not completely understood. The phosphorylation of proteins on the serine or threonine residues that immediately precede proline (pSer/Thr-Pro) is specifically catalyzed by the prolyl isomerase Pin1 and is a key signaling mechanism in cell proliferation and transformation. Here, we found that Pin1 interacts with mitogen-activated protein kinase/extracellular signal-regulated kinase kinase (MEK) protein kinase 1, resulting in the induction of HER-2 expression. Pin1(-/-) mouse embryonic fibroblasts exhibited a decrease in epidermal growth factor (EGF)-induced MEK1/2 phosphorylation compared with Pin1(+/+) mouse embryonic fibroblast. In addition, a knockdown of Pin1 resulted in the inhibition of MEK1/2 phosphorylation induced by EGF in MCF-7 cells. Furthermore, PD98059, a specific inhibitor of MEK1/2, and Juglone, a potent Pin1 inhibitor, markedly suppressed the expression of activator protein-2alpha and the HER-2 promoter activity induced by EGF or 12-O-tetradecanoylphorbol-13-acetate in MCF-7 cells. Importantly, these inhibitors inhibited the neoplastic cell transformation induced by EGF in Pin1-overexpressing JB6 Cl41 cells, which showed enhanced cellular formation compared with the control cells. Therefore, Juglone and PD98059 inhibited the colony formation of MCF-7 breast cancer cells in soft agar. These results indicate that Pin1 amplifies EGF signaling in breast cancer cells through its interaction with MEK1 and then enhances HER-2 expression, suggesting that Pin1 plays an important role in the overexpression of HER-2 through Pin1-MEK1-activator protein-2alpha signaling in breast cancer.
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PMID:The prolyl isomerase Pin1 enhances HER-2 expression and cellular transformation via its interaction with mitogen-activated protein kinase/extracellular signal-regulated kinase kinase 1. 2017 61

Although recurrent gene fusions involving erythroblastosis virus E26 transformation-specific (ETS) family transcription factors are common in prostate cancer, their products are considered 'undruggable' by conventional approaches. Recently, rare targetable gene fusions involving the anaplastic lymphoma receptor tyrosine kinase (ALK) gene, have been identified in 1-5% of lung cancers, suggesting that similar rare gene fusions may occur in other common epithelial cancers, including prostate cancer. Here we used paired-end transcriptome sequencing to screen ETS rearrangement-negative prostate cancers for targetable gene fusions and identified the SLC45A3-BRAF (solute carrier family 45, member 3-v-raf murine sarcoma viral oncogene homolog B1) and ESRP1-RAF1 (epithelial splicing regulatory protein-1-v-raf-1 murine leukemia viral oncogene homolog-1) gene fusions. Expression of SLC45A3-BRAF or ESRP1-RAF1 in prostate cells induced a neoplastic phenotype that was sensitive to RAF and mitogen-activated protein kinase kinase (MAP2K1) inhibitors. Screening a large cohort of patients, we found that, although rare, recurrent rearrangements in the RAF pathway tend to occur in advanced prostate cancers, gastric cancers and melanoma. Taken together, our results emphasize the key role of RAF family gene rearrangements in cancer, suggest that RAF and MEK inhibitors may be useful in a subset of gene fusion-harboring solid tumors and demonstrate that sequencing of tumor transcriptomes and genomes may lead to the identification of rare targetable fusions across cancer types.
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PMID:Rearrangements of the RAF kinase pathway in prostate cancer, gastric cancer and melanoma. 2083 79

The inhibitory epidermal growth factor receptor (EGFR) antibody, cetuximab, is an approved therapy for head and neck squamous cell carcinoma (HNSCC). Despite tumor response observed in some HNSCC patients, cetuximab alone or combined with radio- or chemotherapy fails to yield long-term control or cures. We hypothesize that a flexible receptor tyrosine kinase coactivation signaling network supports HNSCC survival in the setting of EGFR blockade, and that drugs disrupting this network will provide superior tumor control when combined with EGFR inhibitors. In this work, we submitted EGFR-dependent HNSCC cell lines to RNA interference-based functional genomics screens to identify, in an unbiased fashion, essential protein kinases for growth and survival as well as synthetic lethal targets for combined inhibition with EGFR antagonists. Mechanistic target of rapamycin kinase (MTOR) and erythroblastosis oncogene B (ERBB)3 were identified as high-ranking essential kinase hits in the HNSCC cell lines. MTOR dependency was confirmed by distinct short hairpin RNAs (shRNAs) and high sensitivity of the cell lines to AZD8055, whereas ERBB3 dependency was validated by shRNA-mediated silencing. Furthermore, a synthetic lethal kinome shRNA screen with a pan-ERBB inhibitor, AZD8931, identified multiple components of the extracellular signal-regulated kinase (ERK) mitogen-activated protein kinase pathway, consistent with ERK reactivation and/or incomplete ERK pathway inhibition in response to EGFR inhibitor monotherapy. As validation, distinct mitogen-activated protein kinase kinase (MEK) inhibitors yielded synergistic growth inhibition when combined with the EGFR inhibitors, gefitinib and AZD8931. The findings identify ERBB3 and MTOR as important pharmacological vulnerabilities in HNSCC and support combining MEK and EGFR inhibitors to enhance clinical efficacy in HNSCC. SIGNIFICANCE STATEMENT: Many cancers are driven by nonmutated receptor tyrosine kinase coactivation networks that defy full inhibition with single targeted drugs. This study identifies erythroblastosis oncogene B (ERBB)3 as an essential protein kinase in epidermal growth factor receptor-dependent head and neck squamous cell cancer (HNSCC) cell lines and a synthetic lethal interaction with the extracellular signal-regulated kinase mitogen-activated protein kinase pathway that provides a rationale for combining pan-ERBB and mitogen-activated protein kinase inhibitors as a therapeutic approach in subsets of HNSCC.
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PMID:Functional RNAi Screens Define Distinct Protein Kinase Vulnerabilities in EGFR-Dependent HNSCC Cell Lines. 3275 51