Structures of human MAP kinase kinase 1 (MEK1) and MEK2 describe novel noncompetitive kinase inhibition

Ohren, Jeffrey F.; Chen, Huifen; Pavlovsky, A.G.; Whitehead, Christopher; Zhang, Erli; Kuffa, Peter; Yan, Chunhong; McConnell, Patrick I.; Spessard, Cindy; Banotai, Craig; Mueller, W. Thomas; Delaney, Amy M.; Omer, Charles A.; Sebolt–Leopold, Judith S.; Dudley, David T.; Leung, Iris; Flamme, Cathlin; Warmus, Joseph S.; Kaufman, Michael D.; Barrett, Stephen D.; Tecle, Haile; Hasemann, Charles A.

doi:10.1038/nsmb859

Cited by 575 publications

(497 citation statements)

References 37 publications

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“…7, A-C, data not shown). Loop 1, in particular, is a stretch of all-negative residues that could potentially interact with residues of MKK7 involved in binding to the three-phosphate group of ATP (27,30). This hypothesis is strongly supported by experimental evidence, because the basic residue-rich region 132-156 (comprising ␤2 and ␤3) was previously identified as a dominant Gadd45␤-binding site of MKK7 (11).…”

Section: Gadd45␤ Regions Mediating Suppression Of Tnf␣-induced Pcd-supporting

confidence: 56%

“…8; also supplementary Fig. S4) (27,30). Indeed, in this model, the ATP-binding site of MKK7 is formed by a number of highly conserved residues (27,30).…”

Section: Gadd45␤ Regions Mediating Suppression Of Tnf␣-induced Pcd-mentioning

confidence: 99%

“…39.4%). This is because the x-ray structure of MEK-1 was resolved in the presence of a non-competitive antagonist, which caused a peculiar deformation of the catalytic site (30). The sequence of MEK-1 was, nevertheless, utilized for multiple alignment with TAO2 and MKK7, to facilitate correct positioning of conserved residues during model building (supplementary Fig.…”

Section: Gadd45␤ Regions Mediating Suppression Of Tnf␣-induced Pcd-mentioning

confidence: 99%

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Insights into the Structural Basis of the GADD45β-mediated Inactivation of the JNK Kinase, MKK7/JNKK2

Papa

Monti

Vitale

et al. 2007

Journal of Biological Chemistry

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NF-B/Rel factors control programmed cell death (PCD), and this control is crucial to oncogenesis, cancer chemoresistance, and antagonism of tumor necrosis factor (TNF) ␣-induced killing. With TNF␣, NF-B-mediated protection involves suppression of the c-Jun-N-terminal kinase (JNK) cascade, and we have identified Gadd45␤, a member of the Gadd45 family, as a pivotal effector of this activity of NF-B. Inhibition of TNF␣-induced JNK signaling by Gadd45␤ depends on direct targeting of the JNK kinase, MKK7/JNKK2. The mechanism by which Gadd45␤ blunts MKK7, however, is unknown. Here we show that Gadd45␤ is a structured protein with a predicted four-stranded ␤-sheet core, five ␣-helices, and two acidic loops. Association of Gadd45␤ with MKK7 involves a network of interactions mediated by its putative helices ␣3 and ␣4 and loops 1 and 2. Whereas ␣3 appears to primarily mediate docking to MKK7, loop 1 and ␣4-loop 2 seemingly afford kinase inactivation by engaging the ATP-binding site and causing conformational changes that impede catalytic function. These data provide a basis for Gadd45␤-mediated blockade of MKK7, and ultimately, TNF␣-induced PCD. They also have important implications for treatment of widespread diseases.

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Section: Gadd45␤ Regions Mediating Suppression Of Tnf␣-induced Pcd-supporting

confidence: 56%

“…8; also supplementary Fig. S4) (27,30). Indeed, in this model, the ATP-binding site of MKK7 is formed by a number of highly conserved residues (27,30).…”

Section: Gadd45␤ Regions Mediating Suppression Of Tnf␣-induced Pcd-mentioning

confidence: 99%

Section: Gadd45␤ Regions Mediating Suppression Of Tnf␣-induced Pcd-mentioning

confidence: 99%

See 1 more Smart Citation

Insights into the Structural Basis of the GADD45β-mediated Inactivation of the JNK Kinase, MKK7/JNKK2

Papa

Monti

Vitale

et al. 2007

Journal of Biological Chemistry

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“…Structural studies with an analog of CI-1040 in complex with MEK1 or MEK2 showed inhibitor binding did not perturb ATP binding, and instead, bound to a unique inhibitor binding pocket adjacent to the ATP-binding site (Ohren et al, 2004). Inhibitor binding locked MEK in a catalytically inactive conformation.…”

Section: Mek Inhibitorsmentioning

confidence: 99%

Targeting the Raf-MEK-ERK mitogen-activated protein kinase cascade for the treatment of cancer

2007

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“…MEK inhibitors are very specific and do not inhibit many different protein kinases including p38 MAPK and JNK (Davies et al, 2000). The crystal structures of MEK1 and MEK2 have been determined as ternary complexes with ATP and PD184352 and have revealed that both MEK1 and MEK2 have unique inhibitor binding sites located on a hydrophobic pocket adjacent to but not overlapping with the ATP binding site (Ohren et al, 2004). Furthermore, effective targeting of MEK1,2 is highly specific as ERK1,2 are the only well-described downstream targets.…”

Section: Therapeutic Targeting Of the Pi3k/akt/pten/mtor And Raf/mek/mentioning

confidence: 99%

Alteration of Akt activity increases chemotherapeutic drug and hormonal resistance in breast cancer yet confers an achilles heel by sensitization to targeted therapy

McCubrey

Sokolosky

Lehmann

et al. 2008

Advances in Enzyme Regulation

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The PI3K/PTEN/Akt/mTOR pathway plays critical roles in the regulation of cell growth. The effects of this pathway on drug resistance and cellular senescence of breast cancer cells has been a focus of our laboratory. Introduction of activated Akt or mutant PTEN constructs which lack lipid phosphatase [PTEN(G129E)] or lipid and protein phosphatase [PTEN(C124S)] activity increased the resistance of the cells to the chemotherapeutic drug doxorubicin, and the hormonal drug tamoxifen. Activated Akt and PTEN genes also inhibited the induction of senescence after doxorubicin treatment; a phenomenon associated with unrestrained proliferation and tumorigenesis. Interference with the lipid phosphatase domain of PTEN was sufficient to activate Akt/mTOR/p70S6K as MCF-7 cells transfected with the mutant PTEN gene lacking the lipid phosphatase activity [PTEN(G129E)] displayed elevated levels of activated Akt and p70S6K compared to empty vector transfected cells. Cells transfected with mutant PTEN or Akt constructs were hypersensitive to mTOR inhibitors when compared with the parental or empty vector transfected cells. Akt-transfected cells were cultured for over two months in tamoxifen from which tamoxifen and doxorubicin resistant cells were isolated that were >10-fold more resistant to tamoxifen and doxorubicin than the original Akt-transfected cells. These cells had a decreased induction of both activated p53 and total p21 Cip1 upon doxorubicin treatment. Furthermore, these cells had an increased inactivation of GSK-3β and decreased expression of the estrogen receptor-α. In these drug resistant cells, there was an increased activation Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errorsmaybe discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. of ERK which is associated with proliferation. These drug resistant cells were hypersensitive to mTOR inhibitors and also sensitive to MEK inhibitors, indicating that the enhanced p70S6K and ERK expression was relevant to their drug and hormonal resistance. Given that Akt is overexpressed in greater than 50% of breast cancers, our results point to potential therapeutic targets, mTOR and MEK. These studies indicate that activation of the Akt kinase or disruption of the normal activity of the PTEN phosphatase can have dramatic effects on activity of p70S6K and other downstream substrates and thereby altering the therapeutic sensitivity of breast cancer cells. The effects of doxorubicin and tamoxifen on induction of the Raf/MEK/ERK and PI3K/Akt survival pathways were examined in unmodified MCF-7 breast cells. Doxorubicin was a potent inducer of activated ERK and to a lesser extent Akt. Tamoxifen also in...

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Structures of human MAP kinase kinase 1 (MEK1) and MEK2 describe novel noncompetitive kinase inhibition

Cited by 575 publications

References 37 publications

Insights into the Structural Basis of the GADD45β-mediated Inactivation of the JNK Kinase, MKK7/JNKK2

Insights into the Structural Basis of the GADD45β-mediated Inactivation of the JNK Kinase, MKK7/JNKK2

Targeting the Raf-MEK-ERK mitogen-activated protein kinase cascade for the treatment of cancer

Alteration of Akt activity increases chemotherapeutic drug and hormonal resistance in breast cancer yet confers an achilles heel by sensitization to targeted therapy

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