A Mammalian Scaffold Complex That Selectively Mediates MAP Kinase Activation

Whitmarsh, Alan J.; Cavanagh, Julie; Tournier, Cathy; Yasuda, Jun; Davis, Roger J.

doi:10.1126/science.281.5383.1671

Cited by 621 publications

(556 citation statements)

References 22 publications

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“…In this study, the activity of RhoA is in part regulated by the enhanced p190RhoGEF expression after CD40 ligation. However, a recent study on neuronal cells also showed that p190RhoGEF can directly bind to the c-Jun N-terminal kinase (JNK)-interacting protein, JIP-1 (13), which is reported to serve as a substrate for JNK (19) and as a scaffolding protein for JNK activation (20). Therefore, further study will be required to determine the possibility that p190RhoGEF may control a wider range of cellular processes than those that are predicted by its GDP/GTP exchange activity.…”

Section: Overexpression Of P190rhogef Enhances the Nf-b Activationmentioning

confidence: 99%

Cutting Edge: Induced Expression of a RhoA-Specific Guanine Nucleotide Exchange Factor, p190RhoGEF, Following CD40 Stimulation and WEHI 231 B Cell Activation

Lee

Kim

2003

The Journal of Immunology

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Stimulation of the B cell surface receptor CD40 induces transcriptional activation and protein expression. To determine which proteins are required for the CD40-mediated B cell activation, we performed a two-dimensional gel electrophoresis of the WEHI 231 B cell lysates. We report in this study the identification of one protein in which the expression was remarkably induced following CD40 stimulation. It was the p190 Rho guanine nucleotide exchange factor (GEF), p190RhoGEF, a recently identified GEF that is specific for RhoA. Overexpression of either p190RhoGEF or RhoA (Q63L), a constitutively active form of RhoA, mimics the effects of CD40 stimulation, such as changes in cellular structure and NF-κB activation. These p190RhoGEF overexpression effects are abrogated when coexpressed with a dominant negative form of RhoA (T19N). We also provide evidence for the CD40-mediated cellular changes that are abrogated in cells that are overexpressed with the dominant negative form of either p190RhoGEF (Y1003A) or RhoA (T19N).

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Section: Overexpression Of P190rhogef Enhances the Nf-b Activationmentioning

confidence: 99%

Cutting Edge: Induced Expression of a RhoA-Specific Guanine Nucleotide Exchange Factor, p190RhoGEF, Following CD40 Stimulation and WEHI 231 B Cell Activation

Lee

Kim

2003

The Journal of Immunology

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“…When overexpressed in mammalian cells, MLK3 activates JNK via the phosphorylation and activation of SEK/MKK4 (Rana et al, 1996) or MKK7 (Whitmarsh et al, 1998). Moreover, putative scaffold proteins, JIP-1 (JNK interacting protein-1) and JIP-2 have recently been identified and shown to interact in a specific manner with members of the MLK family and with MKK7 and JNK, but not with Cdc42, thereby linking these kinase-signaling components (Dickens et al, 1997;Whitmarsh et al, 1998;Yasuda et al, 1999). MLK3 has also been shown to activate the MAPK p38 kinase pathway via MKK3/6 (Tibbles et al, 1996) and the extracellular signal-related protein kinase (ERK) pathway (Hartkamp et al, 1999).…”

Section: Abstract: Apoptosis; Cdc42; Mlk3; Signal Transduction; Sympmentioning

confidence: 99%

Evidence for a Role of Mixed Lineage Kinases in Neuronal Apoptosis

et al. 2001

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Superior cervical ganglion (SCG) sympathetic neurons die by apoptosis when deprived of nerve growth factor (NGF). It has been shown previously that the induction of apoptosis in these neurons at NGF withdrawal requires both the activity of the small GTP-binding protein Cdc42 and the activation of the c-Jun N-terminal kinase (JNK) pathway. The mixed lineage kinase 3 (MLK3) belongs to a family of mitogen-activated protein (MAP) kinase kinase kinases. MLK3 contains a Cdc42/Rac interactive-binding (CRIB) domain and activates both the JNK and the p38 MAP kinase pathways. In this study the role of MLK3 in the induction of apoptosis in sympathetic neurons has been investigated. Overexpression of an active MLK3 induces activation of the JNK pathway and apoptosis in SCG neurons. In addition, overexpression of kinase dead mutants of MLK3 blocks apoptosis as well as c-Jun phosphorylation induced by NGF deprivation. More importantly, MLK3 activity seems to increase by 5 hr after NGF withdrawal in both differentiated PC12 cells and SCG neurons. We also show that MLK3 lies downstream of Cdc42 in the neuronal death pathway. Regulation of MLK3 in neurons seems to be dependent on MLK3 activity and possibly on an additional cellular component, but not on its binding to Cdc42. These results suggest that MLK3, or a closely related kinase, is a physiological element of NGF withdrawal-induced activation of the Cdc42-c-Jun pathway and neuronal death. MLK3 therefore could be an interesting therapeutic target in a number of neurodegenerative diseases involving neuronal apoptosis. Key words: apoptosis; Cdc42; MLK3; signal transduction; sympathetic neurons; Jun kinaseActivation of the c-Jun transcriptional pathway has been shown to be an important regulator of apoptosis of sympathetic neurons induced by nerve growth factor (NGF) withdrawal by both microinjection of antibodies against c-Jun or expression of a c-Jun dominant negative mutant (Estus et al., 1994;Ham et al., 1995). Consistent with these observations, removal of survival factors leads to the activation of c-Jun N-terminal kinase (JNK), either alone or together with p38 mitogen-activated kinase, in a number of neuronal death paradigms, including PC12 cells (Xia et al., 1995), superior cervical ganglion (SCG) neurons (Ham et al., 1995;Eilers et al., 1998), and embryonic motoneurons (Maroney et al., 1998). In addition, phosphorylation of c-Jun and activation of JNK have been observed after neuronal injury in the adult rat brain (Herdegen et al., 1998) (for review, see Mielke and Herdegen, 2000). Taken together, these studies demonstrate that the pathways regulating both the level of c-Jun and its phosphorylation are crucial for the induction of neuronal cell death. Therefore, we were interested in identifying the upstream signaling pathways regulating the activation of the JNK-c-Jun pathway in neurons.Recently, we have shown that, in rat SCG neurons, the Rholike GTPases, Cdc42 and Rac1, are required for NGF withdrawal-induced death and that they induce apoptosis via activation of ...

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“…No proteins providing these associations have been identified, and no information exists about interactions of the nuclear envelope membranes and the cytoskeleton in plants. Compartmentalization of molecular events is the emerging theme in many research areas both for nuclear events, such as replication or transcription (Wei et al, 1998), and, more recently, for cytoplasmic events, such as mitogenactivated kinase pathways (Whitmarsh et al, 1998). In contrast, our knowledge about the cellular structures possibly providing such a compartmentalization and about their dynamic interactions is still in its infancy.…”

Section: Mfp1 and The Mab6c6 Antigen Define A Connection Between The mentioning

confidence: 99%

Matrix Attachment Region Binding Protein MFP1 Is Localized in Discrete Domains at the Nuclear Envelope

Gindullis

Meier

1999

Plant Cell

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Recently, it has been suggested that nuclear processes, such as replication, transcription, and splicing, are spatially organized and associated with a nuclear framework called the nuclear matrix, a structure of unknown molecular composition. It has been shown that chromatin is attached to the nuclear matrix via specific DNA fragments called matrix attachment regions (MARs). We have begun to dissect the plant nuclear matrix by isolating a DNA binding protein with specific affinity for MARs. Here, it is shown that MAR binding filament-like protein 1 (MFP1) is associated with specklelike structures at the nuclear periphery that are part of isolated nuclei and the nuclear matrix. A predicted N-terminal transmembrane domain is necessary for the specific targeting of MFP1 to the speckles, indicating an association with the nuclear envelope-endoplasmic reticulum continuum. In addition, it is shown that a marker protein for plant microtubule organizing centers, which has been shown to be localized on the outside of the plant nuclear envelope, is also part of the nuclear matrix. These findings indicate a close and previously undescribed connection in plants between the nuclear envelope and the internal nuclear matrix, and they suggest a function for MFP1 in attaching chromatin to specific sites at the nuclear periphery. INTRODUCTIONThe nuclear matrix hypothesis proposes a structural framework for the eukaryotic nucleus that is similar to the cytoskeleton. Biochemically, the nuclear matrix is defined as the insoluble material that remains after extraction of nuclei with high-salt solutions (Berezney and Coffey, 1974) or with the chaotropic agent lithium diiodosalicylate (Mirkovitch et al., 1984) and treatment with DNases. Electron microscopy has shown a network of fibers of ‫ف‬ 10 nm in diameter. These fibers resemble the intermediate filaments of the cytoskeleton. Because they can be detected only under certain preparation conditions (He et al., 1990), their in vivo existence has been somewhat controversial.The isolated nuclear matrix binds specifically to certain DNA elements called matrix attachment regions (MARs). MARs are generally AT-rich DNA sequences that are several hundred base pairs long and are localized in the noncoding regions of the DNA, often flanking genes (Gasser and Laemmli, 1987). MARs have a positive effect on gene expression (Allen et al., 1993(Allen et al., , 1996Mlynárová et al., 1996) that is believed to be due to the establishment of independent and transcriptionally active chromatin domains between two MARs (Spiker and Thompson, 1996). Although the nuclear matrix was identified more than 20 years ago (Berezney and Coffey, 1974), none of its structural components has been isolated and molecularly characterized from any organism. One strategy to identify such components has been to isolate proteins that specifically bind to MARs. A small number of MAR binding proteins have been purified and cloned from animals, and they subsequently have been shown to be localized in the nuclear matrix (von Kri...

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A Mammalian Scaffold Complex That Selectively Mediates MAP Kinase Activation

Cited by 621 publications

References 22 publications

Cutting Edge: Induced Expression of a RhoA-Specific Guanine Nucleotide Exchange Factor, p190RhoGEF, Following CD40 Stimulation and WEHI 231 B Cell Activation

Cutting Edge: Induced Expression of a RhoA-Specific Guanine Nucleotide Exchange Factor, p190RhoGEF, Following CD40 Stimulation and WEHI 231 B Cell Activation

Evidence for a Role of Mixed Lineage Kinases in Neuronal Apoptosis

Matrix Attachment Region Binding Protein MFP1 Is Localized in Discrete Domains at the Nuclear Envelope

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