更新于：2024-11-01

MEK1 x MAP2K5 x MEK2

更新于：2024-11-01

基本信息

关联

项与 MEK1 x MAP2K5 x MEK2 相关的药物

SC-1-151 (Duquesne University)

靶点

MAP2K5 x MEK1 x MEK2

作用机制

MAP2K5抑制剂 [+2]

在研机构

Tulane University Hospital & Clinic [+1]

原研机构

Duquesne University of The Holy Spirit

在研适应症

肿瘤

非在研适应症-

最高研发阶段临床前

首次获批国家/地区-

首次获批日期1800-01-20

100 项与 MEK1 x MAP2K5 x MEK2 相关的临床结果

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100 项与 MEK1 x MAP2K5 x MEK2 相关的转化医学

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0 项与 MEK1 x MAP2K5 x MEK2 相关的专利（医药）

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项与 MEK1 x MAP2K5 x MEK2 相关的文献（医药）

2018-04-01·Plant Physiology1区 · 生物学

BRASSINOSTEROID-SIGNALING KINASE1 Phosphorylates MAPKKK5 to Regulate Immunity in Arabidopsis

1区 · 生物学

Article

作者: Li, Juan ; Tang, Dingzhong ; Yan, Haojie ; Shi, Hua ; Wang, Yingchun ; Zhao, Yaofei

Arabidopsis (Arabidopsis thaliana) immune receptor FLAGELLIN SENSING2 (FLS2) rapidly forms a complex to activate pathogen-associated molecular pattern-triggered immunity (PTI) upon perception of the bacterial protein flagellin. The receptor-like cytoplasmic kinase BRASSINOSTEROID-SIGNALINGKINASE1 (BSK1) interacts with FLS2 and is critical for the activation of PTI. However, it is unknown how BSK1 transduces signals to activate downstream immune responses. We identified MEK Kinase5 (MAPKKK5) as a potential substrate of BSK1 by whole-genome phosphorylation analysis. In addition, we demonstrated that BSK1 interacts with and phosphorylates MAPKKK5. In the bsk1-1 mutant, the Ser-289 residue of MAPKKK5 was not phosphorylated as it was in the wild type. Similar to the bsk1 mutant, the mapkkk5 mutant displayed enhanced susceptibility to virulent and avirulent strains of the bacterial pathogen Pseudomonas syringae pv tomato DC3000, and to the fungal powdery mildew pathogen Golovinomyces cichoracearum Phosphorylation of the Ser-289 residue is not involved in MAPKKK5-triggered cell death but is critical for MAPKKK5-mediated resistance to both bacterial and fungal pathogens. Furthermore, MAPKKK5 interacts with multiple MAPK kinases, including MKK1, MKK2, MKK4, MKK5, and MKK6. Overall, these results indicate that BSK1 regulates plant immunity by phosphorylating MAPKKK5 and suggest a direct regulatory mode of signaling from the immune complex to the MAPK cascade.

2014-05-22·Nature1区 · 综合性期刊

Copper is required for oncogenic BRAF signalling and tumorigenesis

1区 · 综合性期刊

Article

作者: Yao, Xiaojie ; Thiele, Dennis J ; Campbell, Sharon L ; Knapp, Stefan ; Xiao, Kunhong ; Brady, Donita C ; Counter, Christopher M ; Turski, Michelle L ; Hobbs, G Aaron ; Crowe, Matthew S ; Chaikuad, Apirat

The BRAF kinase is mutated, typically Val 600→Glu (V600E), to induce an active oncogenic state in a large fraction of melanomas, thyroid cancers, hairy cell leukaemias and, to a smaller extent, a wide spectrum of other cancers. BRAF(V600E) phosphorylates and activates the MEK1 and MEK2 kinases, which in turn phosphorylate and activate the ERK1 and ERK2 kinases, stimulating the mitogen-activated protein kinase (MAPK) pathway to promote cancer. Targeting MEK1/2 is proving to be an important therapeutic strategy, given that a MEK1/2 inhibitor provides a survival advantage in metastatic melanoma, an effect that is increased when administered together with a BRAF(V600E) inhibitor. We previously found that copper (Cu) influx enhances MEK1 phosphorylation of ERK1/2 through a Cu-MEK1 interaction. Here we show decreasing the levels of CTR1 (Cu transporter 1), or mutations in MEK1 that disrupt Cu binding, decreased BRAF(V600E)-driven signalling and tumorigenesis in mice and human cell settings. Conversely, a MEK1-MEK5 chimaera that phosphorylated ERK1/2 independently of Cu or an active ERK2 restored the tumour growth of murine cells lacking Ctr1. Cu chelators used in the treatment of Wilson disease decreased tumour growth of human or murine cells transformed by BRAF(V600E) or engineered to be resistant to BRAF inhibition. Taken together, these results suggest that Cu-chelation therapy could be repurposed to treat cancers containing the BRAF(V600E) mutation.

2007-01-20·Journal of Comparative Neurology3区 · 医学

Differential mRNA distribution of components of the ERK/MAPK signalling cascade in the adult mouse brain

3区 · 医学

Article

作者: Sabine M. Hölter ; Christiane Hitz ; Ralf Kühn ; Wolfgang Wurst ; Barbara Di Benedetto ; Daniela M. Vogt Weisenhorn

AbstractThe mitogen‐activated protein kinases (MAPKs), also called extracellular signal‐regulated kinases (ERKs), are a group of serine/threonine terminal protein kinases activated downstream of a pleiotrophy of transmembrane receptors. Main intracellular components of the MAPK signalling pathway are the RAF, MEK, and ERK proteins, which work in a cascade of activator and effector proteins. They regulate many fundamental cellular functions, including cell proliferation, cell survival, and cell differentiation by transducing extracellular signals to cytoplasmic and nuclear effectors. To reveal more details about possible activation cascades in this pathway, the present study gives a complete description of the differential expression of Braf, Mek1, Mek2, Mek5, Erk1, Erk2, Erk3, and Erk5 in the adult murine brain by way of in situ hybridization analysis. In this study, we found that each gene is widely expressed in the whole brain, except for Mek2, but each displays a very distinct expression pattern, leading to distinct interactions of the MAPK components within different regions. Most notably we found that 1) Braf and Erk3 are coexpressed in the hippocampus proper, confirming a possible functional interaction; 2) in most forebrain areas, Mek5 and Erk5 are coexpressed; and 3) in the neurogenic regions of the brain, namely, the olfactory bulb and the dentate gyrus, Braf is absent, indicating that other activator proteins have to take over its function. Despite these differences, our results show widespread coexpression of the pathway components, thereby confirming the hypothesis of redundant functions among several MEK and ERK proteins in some regions of the brain. J. Comp. Neurol. 500:542–556, 2007. © 2006 Wiley‐Liss, Inc.