TAK1–TAB1 fusion protein: a novel constitutively active mitogen-activated protein kinase kinase kinase that stimulates AP-1 and NF-κB signaling pathways

The Raf protein kinases are major effectors of Ras GTPases and key components of the transcriptional response to serum factors, acting at least in part through the extracellular signal-regulated kinase/mitogen-activated protein kinase pathway. It has recently been suggested that Raf also may trigger other as yet uncharacterized signaling pathways. Here, we have used cDNA microarrays to dissect changes in gene expression induced by activation of inducible c-Raf-1 constructs in human mammary epithelial and ovarian epithelial cells. The majority of Raf-induced transcriptional responses are shown to be blocked by pharmacological inhibition of the Raf substrate mitogen-activated protein kinase kinase, indicating that potential mitogen-activated protein kinase kinase-independent Raf signaling pathways have no significant influence on gene expression. In addition, we used epidermal growth factor receptor inhibitory drugs to address the contribution of autocrine signaling by Raf-induced EGF family proteins to the Raf transcriptional response. At least one-half of the transcription induced by Raf activation requires epidermal growth factor (EGF) receptor function The EGF receptor-independent component of the Raf transcriptional response is entirely up-regulation of gene expression, whereas the EGF receptor-dependent component is an equal mixture of up- and down-regulation. The use of transcriptional profiling in this way allows detailed analysis of the architecture of signaling pathways to be undertaken.

Download Full-text

Inhibition of a signaling pathway in cardiac muscle cells by active mitogen-activated protein kinase kinase.

Molecular Biology of the Cell ◽

10.1091/mbc.6.11.1479 ◽

1995 ◽

Vol 6 (11) ◽

pp. 1479-1490 ◽

Cited By ~ 56

Author(s):

J Thorburn ◽

M Carlson ◽

S J Mansour ◽

K R Chien ◽

N G Ahn ◽

...

Keyword(s):

Gene Expression ◽

Protein Kinase ◽

Cardiac Muscle ◽

Map Kinases ◽

Mitogen Activated Protein Kinase ◽

Cardiac Muscle Cells ◽

Erk Activation ◽

Mitogen Activated Protein ◽

Protein Kinase Kinase ◽

Constitutively Active

Signaling via the Ras pathway involves sequential activation of Ras, Raf-1, mitogen-activated protein kinase kinase (MKK), and the extracellular signal-regulated (ERK) group of mitogen-activated protein (MAP) kinases. Expression from the c-Fos, atrial natriuretic factor (ANF), and myosin light chain-2 (MLC-2) promoters during phenylephrine-induced cardiac muscle cell hypertrophy requires activation of this pathway. Furthermore, constitutively active Ras or Raf-1 can mimic the action of phenylephrine in inducing expression from these promoters. In this study, we tested whether constitutively active MKK, the molecule immediately downstream of Raf, was sufficient to induce expression. Expression of constitutively active MKK induce ERK2 kinase activity and caused expression from the c-Fos promoter, but did not significantly activate expression of reporter genes under the control of either the ANF or MLC-2 promoters. Expression of CL100, a phosphatase that inactivates ERKs, prevented expression from all of the promoters. Taken together, these data suggest that ERK activation is required for expression from the Fos, ANF, and MLC-2 promoters but MKK and ERK activation is sufficient for expression only from the Fos promoter. Constitutively active MKK synergized with phenylephrine to increase expression from a c-Fos- or an AP1-driven reporter. However, active MKK inhibited phenylephrine- and Raf-1-induced expression from the ANF and MLC-2 promoters. A DNA sequence in the MLC-2 promoter that is a target for inhibition by active MKK, but not CL100, was mapped to a previously characterized DNA element (HF1) that is responsible for cardiac specificity. Thus, activation of cardiac gene expression during phenylephrine-induced hypertrophy requires ERK activation but constitutive activation by MKK can inhibit expression by targeting a DNA element that controls the cardiac specificity of gene expression.

Download Full-text

Isorhamnetin inhibits cell proliferation and induces apoptosis in breast cancer via Akt and mitogen-activated protein kinase kinase signaling pathways

Molecular Medicine Reports ◽

10.3892/mmr.2015.4269 ◽

2015 ◽

Vol 12 (5) ◽

pp. 6745-6751 ◽

Cited By ~ 30

Author(s):

SHAN HU ◽

LIMING HUANG ◽

LIWEI MENG ◽

HE SUN ◽

WEI ZHANG ◽

...

Keyword(s):

Breast Cancer ◽

Cell Proliferation ◽

Protein Kinase ◽

Signaling Pathways ◽

Mitogen Activated Protein Kinase ◽

Kinase Signaling ◽

Mitogen Activated Protein ◽

Protein Kinase Kinase

Download Full-text

Impaired CD28-mediated Interleukin 2 Production and Proliferation in Stress Kinase SAPK/ERK1 Kinase (SEK1)/Mitogen-activated Protein Kinase Kinase 4 (MKK4)-deficient T Lymphocytes

Journal of Experimental Medicine ◽

10.1084/jem.186.6.941 ◽

1997 ◽

Vol 186 (6) ◽

pp. 941-953 ◽

Cited By ~ 92

Author(s):

Hiroshi Nishina ◽

Martin Bachmann ◽

Antonio J. Oliveira-dos-Santos ◽

Ivona Kozieradzki ◽

Klaus D. Fischer ◽

...

Keyword(s):

T Cells ◽

Protein Kinase ◽

B Cell ◽

Signaling Pathways ◽

Germinal Centers ◽

Mitogen Activated Protein Kinase ◽

Cd28 Costimulation ◽

Peripheral T Cells ◽

Mitogen Activated Protein ◽

Protein Kinase Kinase

The dual specific kinase SAPK/ERK1 kinase (SEK1; mitogen-activated protein kinase kinase 4/Jun NH2 terminal kinase [ JNK] kinase) is a direct activator of stress-activated protein kinases ([SAPKs]/JNKs) in response to CD28 costimulation, CD40 signaling, or activation of the germinal center kinase. Here we show that SEK1−/− recombination-activating gene (RAG)2−/− chimeric mice have a partial block in B cell maturation. However, peripheral B cells displayed normal responses to IL-4, IgM, and CD40 cross-linking. SEK1−/− peripheral T cells showed decreased proliferation and IL-2 production after CD28 costimulation and PMA/Ca2+ ionophore activation. Although CD28 expression was absolutely crucial to generate vesicular stomatitis virus (VSV)-specific germinal centers, SEK1−/−RAG2−/− chimeras mounted a protective antiviral B cell response, exhibited normal IgG class switching, and made germinal centers in response to VSV. Interestingly, PMA/Ca2+ ionophore stimulation, which mimics TCR–CD3 and CD28-mediated signal transduction, induced SAPK/JNK activation in peripheral T cells, but not in thymocytes, from SEK1−/− mice. These results show that signaling pathways for SAPK activation are developmentally regulated in T cells. Although SEK1−/− thymocytes failed to induce SAPK/JNK in response to PMA/Ca2+ ionophore, SEK1−/−RAG2−/− thymocytes proliferated and made IL-2 after PMA/Ca2+ ionophore and CD3/CD28 stimulation, albeit at significantly lower levels compared to SEK1+/+RAG2−/− thymocytes, implying that CD28 costimulation and PMA/Ca2+ ionophore–triggered signaling pathways exist that can mediate proliferation and IL-2 production independently of SAPK activation. Our data provide the first genetic evidence that SEK1 is an important effector molecule that relays CD28 signaling to IL-2 production and T cell proliferation.

Download Full-text