Neurotrophin Receptor-interacting Mage Homologue Is an Inducible Inhibitor of Apoptosis Protein-interacting Protein That Augments Cell Death

Jordan, Bruce W.M.; Dinev, Dragomir; LeMellay, Veronique; Troppmair, Jakob; Rudolf, G.; Wixler, Ludmilla; Sendtner, Michael; Ludwig, Stephan; Rapp, Ulf R.

doi:10.1074/jbc.c100171200

Cited by 81 publications

(52 citation statements)

References 29 publications

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“…It interacts with p75NTR to induce NGF-dependent apoptosis (18), and subsequent studies identified two different mechanisms underlying NRAGE-mediated apoptosis. One is by promoting the degradation of the survival protein XIAP (X-linked inhibitor of apoptosis) (19), and the second is by activating the c-Jun N-terminal kinase and caspase signaling pathway, both of which are known signaling cascades for programmed cell death (20). It is not known whether these two mechanisms operate independently, perhaps in different cell types, or whether NRAGE can induce multiple signals to ensure the demise of the cell.…”

Section: Discussionmentioning

confidence: 99%

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UNC5H1 Induces Apoptosis via Its Juxtamembrane Region through an Interaction with NRAGE

Williams

Strickland

Watanabe

et al. 2003

Journal of Biological Chemistry

102

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The UNC5Hs are axon guidance receptors that mediate netrin-1-dependent chemorepulsion, and dependence receptors that mediate netrin-1-independent apoptosis. Here, we report an interaction between UNC5H1 and NRAGE. Our experiments show that this interaction is responsible for apoptosis induced by UNC5H1, and this level of apoptosis is greater than the amount induced by either UNC5H2 or UNC5H3. We mapped the NRAGE binding domain of UNC5H1 to its ZU-5 domain and show that this region, in addition to an adjacent PEST sequence, is required for UNC5H1-mediated apoptosis. Chimeric UNC5H2 and UNC5H3 receptors, containing the NRAGE binding domain and PEST sequence of UNC5H1, bind NRAGE and cause increased levels of apoptosis. UNC5H1 expression does not induce apoptosis in differentiated PC12 cells, which down-regulate NRAGE, but induces apoptosis in native PC12 cells that endogenously express high levels of NRAGE and in differentiated PC12 cells when NRAGE is overexpressed. Together, these results demonstrate a mechanism for UNC5H1-mediated apoptosis that requires an interaction with the MAGE protein NRAGE.Apoptosis plays a critical role in determining the size and shape of the vertebrate nervous system (1). The execution phase of the apoptotic program in neurons is well characterized and, as with most cell types, depends on the activation of intracellular proteases, primarily caspases (2). In contrast, it is not well understood how cues from the environment regulate this process during development of the nervous system. UNC-5 was originally characterized in Caenorhabditis elegans as a gene required for axonal repulsion in netrin/UNC-6 responsive neurons (3, 4). The vertebrate members of this family (UNC5H1, 2, and 3) (5, 6), together with C. elegans UNC-5 (4) and Drosophila Unc5 (7), comprise a subgroup of the Ig superfamily of receptors. The UNC5s contain two Ig and two thrombospondin type-I repeats in the extracellular domain. In addition, their cytoplasmic domains contain regions of homology with other proteins: 1) a ZU-5 domain homologous to Zona Occludens-1, a protein implicated in tight-junction formation (8); and 2) a C-terminal death domain, a domain first identified as the pro-apoptotic region of tumor necrosis factor receptor-1 (9, 10). In a netrin-1 gradient, a complex of UNC5H1 and DCC mediates repulsion (11), although there is evidence suggesting that short range repulsion by netrin-1 may be mediated by UNC5 alone (3, 7). NRAGE (Dlxin-1, MAGE-D1) is a recently identified molecule belonging to the MAGE (melanoma antigen) protein family. There are currently over 25 MAGE proteins in humans, characterized by the presence of a MAGE homology domain. The expression of many MAGE proteins is restricted to cancer cells (12); however, recent studies have revealed a role for two MAGE proteins in the nervous system. One MAGE family member, necdin, is thought to maintain the differentiated state of post-mitotic neurons by preventing entry into the cell cycle (13,14). Another MAGE family member, NRAGE, is expressed in the...

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Section: Discussionmentioning

confidence: 99%

“…Subsequently, it was found to utilize two mechanisms to induce apoptosis in cells. One involves NRAGE-dependent degradation of the survival protein XIAP (X-linked inhibitor of apoptosis) (19) and the other involves NRAGE-dependent activation of the c-Jun N-terminal kinase signaling pathway and caspases (20).…”

mentioning

confidence: 99%

UNC5H1 Induces Apoptosis via Its Juxtamembrane Region through an Interaction with NRAGE

Williams

Strickland

Watanabe

et al. 2003

Journal of Biological Chemistry

102

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“…A likely candidate for this regulation is the PI3-kinase-Akt pathway, which comprises the major NGF-mediated survival pathway in these neurons . This pathway has been previously shown to directly regulate the level and activation state of the Bcl-2 family (Datta et al, 1997) and to regulate levels of the IAPs (inhibitor of apoptosis) (Wiese et al, 1999;Jordan et al, 2001), thereby providing multiple checkpoints at different levels to ensure that neurons are only eliminated when they have failed to compete successfully for this trophic factor during the period of naturally occurring neuronal death.…”

Section: Discussionmentioning

confidence: 99%

Evidence That ΔNp73 Promotes Neuronal Survival by p53-Dependent and p53-Independent Mechanisms

Lee¹,

Ho²,

Zanassi³

et al. 2004

J. Neurosci.

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The p53 family member, p73, is essential for the survival of sympathetic neurons during the developmental period of naturally occurring neuronal death. Here, we have asked whether ⌬Np73, which is the only p73 isoform expressed in sympathetic neurons, mediates this survival by p53-dependent and/or p53-independent mechanisms. Initially, we used a genetic approach and crossed p53 ϩ/Ϫ and p73 Ϫ/Ϫ mice, and that this decrease is not rescued by the lack of p53, suggesting a role for p73 in regulating cell size that does not involve interactions with p53. Thus, ⌬Np73 promotes neuronal survival via p53-dependent and -independent mechanisms, and it does so at multiple points, including some of the most proximal events that occur after NGF withdrawal.

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“…NRAGE is a p75 NTR-binding protein (46) that regulates cell cycle progression and promotes apoptosis by enhancing the apoptotic effect of the p75 NTR (47,48). NRAGE also interacts with the Msx and Dlx families of homeodomain proteins that are involved in craniofacial, limb, and nervous system development (49).…”

Section: Discussionmentioning

confidence: 99%

DAMAGE, a Novel α-Dystrobrevin-associated MAGE Protein in Dystrophin Complexes

Albrecht

Froehner

2004

Journal of Biological Chemistry

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Mice rendered null for ␣-dystrobrevin, a component of the dystrophin complex, have muscular dystrophy, despite the fact that the sarcolemma remains relatively intact (Grady, R. M., Grange, R. W., Lau, K. S., Maimone, M. M., Nichol, M. C., Stull, J. T., and Sanes, J. R. (1999) Nat. Cell Biol. 1, 215-220) Thus, ␣-dystrobrevin may serve a signaling function that is important for the maintenance of muscle integrity. We have identified a new dystrobrevin-associated protein, DAMAGE, that may play a signaling role in brain, muscle, and peripheral nerve. In humans, DAMAGE is encoded by an intronless gene located at chromosome Xq13.1, a locus that contains genes involved in mental retardation. DAM-AGE associates directly with ␣-dystrobrevin, as shown by yeast two-hybrid, and co-immunoprecipitates with the dystrobrevin-syntrophin complex from brain. This co-immunoprecipitation is dependent on the presence of ␣-dystrobrevin but not ␤-dystrobrevin. The DAMAGE protein contains a potential nuclear localization signal, 30 12-amino acid repeats, and two MAGE homology domains. The domain structure of DAMAGE is similar to that of NRAGE, a MAGE protein that mediates p75 neurotrophin receptor signaling and neuronal apoptosis (Salehi, A. H., Roux, P. P., Kubu, C. J., Zeindler, C., Bhakar, A., Tannis, L. L., Verdi, J. M., and Barker, P. A. (2000) Neuron 27, 279 -288). DAMAGE is highly expressed in brain and is present in the cell bodies and dendrites of hippocampal and Purkinje neurons. In skeletal muscle, DAMAGE is at the postsynaptic membrane and is associated with a subset of myonuclei. DAMAGE is also expressed in peripheral nerve, where it localizes along with other members of the dystrophin complex to the perineurium and myelin. These results expand the role of dystrobrevin and the dystrophin complex in membrane signaling and disease.The dystrophin glycoprotein complex links the actin cytoskeleton to the extracellular matrix in skeletal muscle. In addition, recent studies (1-7) have shown that the dystrophin complex is critical for the localization of a variety of signaling molecules to the skeletal muscle sarcolemma. Thus, the dystrophin complex functions as both a structural link to the extracellular matrix and as a scaffold that concentrates and stabilizes functionally inter-related signaling proteins at the muscle cell membrane.Part of the signaling function of the dystrophin complex may be mediated by the dystrobrevins. The role of the dystrobrevins in signaling is not fully understood; however, targeted disruption of the ␣-dystrobrevin gene in mice results in muscle pathology without the membrane fragility characteristic of dystrophin-deficient muscular dystrophy (8). These findings suggest that ␣-dystrobrevin is important for muscle function but in a non-structural way. Dystrobrevin has no enzymatic activity of its own; therefore, the involvement of dystrobrevin in signaling pathways is dependent on its interaction with other proteins.The dystrobrevins are transcribed from two separate genes, designated ␣ and ␤, that shar...

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Neurotrophin Receptor-interacting Mage Homologue Is an Inducible Inhibitor of Apoptosis Protein-interacting Protein That Augments Cell Death

Cited by 81 publications

References 29 publications

UNC5H1 Induces Apoptosis via Its Juxtamembrane Region through an Interaction with NRAGE

UNC5H1 Induces Apoptosis via Its Juxtamembrane Region through an Interaction with NRAGE

Evidence That ΔNp73 Promotes Neuronal Survival by p53-Dependent and p53-Independent Mechanisms

DAMAGE, a Novel α-Dystrobrevin-associated MAGE Protein in Dystrophin Complexes

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