Crystal Structures of the Mnk2 Kinase Domain Reveal an Inhibitory Conformation and a Zinc Binding Site

Jauch, Ralf; Jäkel, Stefan; Netter, C.; Schreiter, Kay; Aicher, Babette; Jäckle, Herbert; Wahl, Markus C.

doi:10.1016/j.str.2005.07.013

Cited by 63 publications

(106 citation statements)

References 37 publications

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“…This is due to a 180° rotation relative to the DFG motif, which locks the kinase in the DFD-out conformation. This unique structure coupled with specific regions of the catalytic domain (insertions 1-3) distinguishes the Mnks from other kinases and provide an opportunity to design specific Mnk inhibitors [9,61].…”

Section: Dual Targeting Of Mnks Reviewmentioning

confidence: 99%

Dual Abrogation of Mnk and Mtor: A Novel Therapeutic Approach for the Treatment of Aggressive Cancers

2017

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Targeting the translational machinery has emerged as a promising therapeutic option for cancer treatment. Cancer cells require elevated protein synthesis and exhibit augmented activity to meet the increased metabolic demand. Eukaryotic translation initiation factor 4E is necessary for mRNA translation, its availability and phosphorylation are regulated by the PI3K/AKT/mTOR and MNK1/2 pathways. The phosphorylated form of eIF4E drives the expression of oncogenic proteins including those involved in metastasis. In this article, we will review the role of eIF4E in cancer, its regulation and discuss the benefit of dual inhibition of upstream pathways. The discernible interplay between the MNK and mTOR signaling pathways provides a novel therapeutic opportunity to target aggressive migratory cancers through the development of hybrid molecules.

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Section: Dual Targeting Of Mnks Reviewmentioning

confidence: 99%

Dual Abrogation of Mnk and Mtor: A Novel Therapeutic Approach for the Treatment of Aggressive Cancers

2017

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“…However, MNK1 and MNK2 have atypical T-loops as the DFG motif is replaced by DFD, and in the only structures available (MNK2 (7)), the MNK T-loop has out-in conformations requiring a conformational switch to coordinate with Mg 2ϩ /ATP. In the T-loop of MNKs, there is a second Thr-Pro motif, which is conserved even in Drosophila melanogaster Mnk (7). The double alanine mutant of huMNK1 is inactive (T209A/T214A), and the T-loop is phosphorylated at both sites, as assessed by Thr to Ser mutations, peptide mapping, and phosphoamino acid analyses of resolved peptides (8).…”

mentioning

confidence: 99%

MNK1 and MNK2 Regulation in HER2-overexpressing Breast Cancer Lines

Chrestensen

Shuman

Eschenroeder

et al. 2007

Journal of Biological Chemistry

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MAPK-interacting protein kinases 1 and 2 (MNK1 and MNK2) function downstream of p38 and ERK MAPK, but there are large gaps in our knowledge of how MNKs are regulated and function. As proteins activated in the HER2/Ras/Raf/ERK pathway, the MNKs are of potential interest in HER2-overexpressing cancers. We utilized a panel of breast cell lines (HCC1419, AU565, SKBR3, MCF7, and MCF10A), three of which overexpress HER2, to characterize the amounts and activation status of MNKs and other pathway enzymes (ERKs and RSKs) in these cells. We generated a phosphospecific antibody to Thr(P)-214 in the T-loop of MNKs and found that phosphorylations of both Thr-209 and Thr-214 in human MNK1 are required for activation. Increased phosphorylation and activity of the MNKs correlate with HER2 overexpression, and inhibition of the MNKs reduces colony formation in soft agar. Our work identifies the MNKs as potential therapeutic targets for breast cancer treatments.The functional role of MAP 4 kinase-interacting kinase 1 (MNK1) and MNK2 in signal transduction is one of the major unsolved problems in signal transduction (1), and only recently has a MNK1 function been shown in translation of cytokines (2). Likewise, there are still large gaps in our understanding of how MNKs are regulated by MAP kinases. Human MNK1 was cloned as a novel substrate for ERK1, and the phosphorylation site identified was Thr-334 in the C terminus (3).MNK1 and MNK2 contain a canonical Thr-Pro motif for MAPKAP kinases in the T-loop, nine residues N-terminal to the conserved APE motif. Phosphorylation of the canonical Thr-Pro motif is required for activation of the RSK C-terminal domain (4), the MSK1 C-terminal domain (5), and MAPKAP kinase 2 (6). For these MAPKAP kinases, the canonical phosphorylation is the only phosphorylation required in the T-loop. However, MNK1 and MNK2 have atypical T-loops as the DFG motif is replaced by DFD, and in the only structures available (MNK2 (7)), the MNK T-loop has out-in conformations requiring a conformational switch to coordinate with Mg 2ϩ /ATP. In the T-loop of MNKs, there is a second Thr-Pro motif, which is conserved even in Drosophila melanogaster Mnk (7). The double alanine mutant of huMNK1 is inactive (T209A/T214A), and the T-loop is phosphorylated at both sites, as assessed by Thr to Ser mutations, peptide mapping, and phosphoamino acid analyses of resolved peptides (8). The available phosphospecific antibody (Cell Signaling) was made to a proprietary phosphopeptide containing both Thr-209/Thr-214 phospho-sites. The role of the canonical Thr-214 site, in particular, has not been deconvoluted and deserves more study. We investigated regulation of MNK phosphorylation with a phosphospecific antibody we generated for the canonical Thr-214 -Pro as well as the available phospho-Mnk1 (Thr-197/202) antibody (Cell Signaling).Human epidermal growth factor receptor 2 (HER2) (also known as ERBb2/Neu) is frequently overexpressed and/or mutated in aggressive breast cancers (9). HER2 is the molecular target of trastuzumab (Hercep...

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“…Interestingly, we did not identify any Mnk1 subtype-specific inhibitors, further indicating significant structural differences between Mnk1 and Mnk2. Analysis of crystal structures of the Mnk1 and Mnk2 kinase domains (Jauch et al, 2005; suggests that Mnk2 has a larger ATP binding pocket than Mnk1. Our Mnk2-specific inhibitors provide a new opportunity to dissect biologic functions of Mnk1 and Mnk2.…”

Section: Discussionmentioning

confidence: 99%

Identification of a Highly Conserved Allosteric Binding Site on Mnk1 and Mnk2

et al. 2015

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Elevated levels of phosphorylated eukaryotic initiation factor 4E (eIF4E) have been implicated in many tumor types, and mitogen activated protein kinase-interacting kinases (Mnks) are the only known kinases that phosphorylate eIF4E at Ser209. The phosphorylation of eIF4E is essential for oncogenic transformation but is of no significance to normal growth and development. Pharmacological inhibition of Mnks therefore provides a nontoxic and effective strategy for cancer therapy. However, a lack of specific Mnk inhibitors has confounded pharmacological target validation and clinical development. Herein, we report the identification of a novel series of Mnk inhibitors and their binding modes. A systematic workflow has been established to distinguish between type III and type I/II inhibitors. A selection of 66 compounds was tested for Mnk1 and Mnk2 inhibition, and 9 out of 20 active compounds showed type III interaction with an allosteric site of the proteins. Most of the type III inhibitors exhibited dual Mnk1 and Mnk2 activities and demonstrated potent antiproliferative properties against the MV4-11 acute myeloid leukemia cell line. Interestingly, ATP-/ substrate-competitive inhibitors were found to be highly selective for Mnk2, with little or no activity for Mnk1. Our study suggests that Mnk1 and Mnk2 share a common structure of the allosteric inhibitory binding site but possess different structural features of the ATP catalytic domain. The findings will assist in the future design and development of Mnk targeted anticancer therapeutics.

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Crystal Structures of the Mnk2 Kinase Domain Reveal an Inhibitory Conformation and a Zinc Binding Site

Cited by 63 publications

References 37 publications

Dual Abrogation of Mnk and Mtor: A Novel Therapeutic Approach for the Treatment of Aggressive Cancers

Dual Abrogation of Mnk and Mtor: A Novel Therapeutic Approach for the Treatment of Aggressive Cancers

MNK1 and MNK2 Regulation in HER2-overexpressing Breast Cancer Lines

Identification of a Highly Conserved Allosteric Binding Site on Mnk1 and Mnk2

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