Bruce D. Carter

The kinesin KIF1Bβ acts downstream from EglN3 to induce apoptosis and is a potential 1p36 tumor suppressor

VHL, NF-1, c-Ret, and Succinate Dehydrogenase Subunits B and D act on a developmental apoptotic pathway that is activated when nerve growth factor (NGF) becomes limiting for neuronal progenitor cells and requires the EglN3 prolyl hydroxylase as a downstream effector. Germline mutations of these genes cause familial pheochromocytoma and other neural crest-derived tumors. Using an unbiased shRNA screen we found that the kinesin KIF1Bbeta acts downstream from EglN3 and is both necessary and sufficient for neuronal apoptosis when NGF becomes limiting. KIF1Bbeta maps to chromosome 1p36.2, which is frequently deleted in neural crest-derived tumors including neuroblastomas. We identified inherited loss-of-function KIF1Bbeta missense mutations in neuroblastomas and pheochromocytomas and an acquired loss-of-function mutation in a medulloblastoma, arguing that KIF1Bbeta is a pathogenic target of these deletions.

Neurotrophins Live or Let Die: Does p75NTR Decide?

However, enhancing neurotrophin binding is not the Cornell University Medical College only role for p75. A number of reports suggest that it New York, New York 10021 also modulates trk signaling. While it is clear that trk †Growth Factor and Regeneration Group signaling can occur in the absence of p75, the reDepartment of Neuroscience sponses are increased in its presence. For example, Max Delbrück Institute for Molecular Medicine sympathoadrenal cells (MAH cells) expressing only trkA Berlin-Buch D-13122 extended neurites and survived in the presence of NGF Federal Republic of Germany but when coexpressing p75 showed an 8-fold higher

The zinc finger protein NRIF interacts with the neurotrophin receptor p75NTR and participates in programmed cell death

NRIF (neurotrophin receptor interacting factor) is a ubiquitously expressed zinc finger protein of the Krüppel family which interacts with the neurotrophin receptor p75NTR. The interaction was first detected in yeast and then biochemically confirmed using recombinant GST–NRIF fusions and p75NTR expressed by eukaryotic cells. Transgenic mice carrying a deletion in the exon encoding the p75NTR‐binding domain of NRIF display a phenotype which is strongly dependent upon genetic background. While at the F2 generation there is only limited (20%) embryonic lethality, in a congenic BL6 strain nrif−/− mice cannot survive beyond E12, but are viable and healthy to adulthood in the Sv129 background. The involvement of NRIF in p75NTR/NGF‐mediated developmental cell death was examined in the mouse embryonic neural retina. Disruption of the nrif gene leads to a reduction in cell death which is quantitatively indistinguishable from that observed in p75NTR−/− and ngf−/− mice. These results indicate that NRIF is an intracellular p75NTR‐binding protein transducing cell death signals during development.

Neurotrophin receptors: mediators of life and death.

The mechanism of action of NGF has continued to provide a challenging and formidable problem in signal transduction. NGF can bind independently to two different receptors, the trkA tyrosine kinase receptor and the p75 neurotrophin receptor, which are involved in many different signaling events. In addition to promoting cell differentiation survival, NGF can paradoxically be an inducer of cell death. Several receptor mediated mechanisms are proposed to explain how NGF might act as a trophic factor and as a cell killer. The survival and cell death properties of the receptors are dependent upon the relative ratio of receptors and the persistent nature of the signaling events.

Activation of the transcription factor NF-|[kappa]|B in Schwann cells is required for peripheral myelin formation

Peripheral myelin formation is initiated by axonal cues that trigger a differentiation program in associated Schwann cells. Here, we define one essential differentiation signal: activation of the transcription factor NF-κB. In rat sciatic nerves, NF-κB was highly upregulated in pre-myelinating Schwann cells, and then its expression progressively declined until it was nearly absent in adults. Similarly, in co-cultures of Schwann cells and sensory neurons, NF-κB activation paralleled myelination, and blocking its activity or using cells from mice lacking the NF-κB subunit p65 markedly attenuated myelination. Inhibiting NF-κB also prevented activation of Oct-6, a transcription factor induced by axonal contact and required for proper myelin formation. These results show that the activation of NF-κB is an essential signal for the progression of axon-associated Schwann cells into a myelinating phenotype.

Ligand-Dependent Cleavage of the P75 Neurotrophin Receptor Is Necessary for NRIF Nuclear Translocation and Apoptosis in Sympathetic Neurons

The p75 neurotrophin receptor regulates neuronal survival, promoting it in some contexts yet activating apoptosis in others. The mechanism by which the receptor elicits these differential effects is poorly understood. Here, we demonstrate that p75 is cleaved by gamma-secretase in sympathetic neurons, specifically in response to proapoptotic ligands. This cleavage resulted in ubiquitination and subsequent nuclear translocation of NRIF, a DNA binding protein essential for p75-mediated apoptosis. Inhibition of gamma-secretase or expression of a mutant p75 resistant to this protease prevented receptor proteolysis, blocked NRIF nuclear entry, and prevented apoptosis. In contrast, overexpression of the p75 ICD resulted in NRIF nuclear accumulation and apoptosis. The receptor proteolysis and NRIF nuclear localization were also observed in vivo during naturally occurring cell death in the superior cervical ganglia. These results indicate that p75-mediated apoptosis requires gamma-secretase dependent release of its ICD, which facilitates nuclear translocation of NRIF.

The p75 neurotrophin receptor: multiple interactors and numerous functions.

The neurotrophin receptor p75 (p75NTR), is involved in a diverse array of cellular responses, including apoptosis, neurite outgrowth and myelination. Stimulation of p75NTR with neurotrophin can activate multiple downstream signals, including the small GTP binding protein Rac, the transcription factor NF-kappa B and the stress activated kinase, JNK. How these signals are generated and regulated to produce a specific cellular effect has yet to be fully elucidated. A number of proteins have recently been shown to interact with the intracellular domain of p75NTR. Here, we review these p75NTR interacting factors and the current evidence as to how they contribute to the functional effects of p75NTR activation.

A splice variant of the neurotrophin receptor trkB with increased specificity for brain-derived neurotrophic factor.

The trkB gene codes for a receptor tyrosine kinase, which is essential for the development of the peripheral nervous system. This receptor can be activated by three different neurotrophins: BDNF, NT‐4/5 and NT‐3. The extracellular domain of trkB was found to be encoded in 10 exons corresponding to receptor subdomains previously identified on the basis of protein sequence comparisons. Exon 9 was skipped in a novel tyrosine kinase transcript of the trkB gene, designated ctrkB‐Short (ctrkB‐S). While the previously described trkB receptor ctrkB‐Long (ctrkB‐L) and trkB‐S receptors were activated similarly by BDNF, trkB‐S interacted poorly with NT‐4/5 and NT‐3 as measured by ligand binding, ligand‐induced autophosphorylation and ligand‐dependent activation of p21ras. Efficient activation of ctrkB‐S by NT‐3 was restored by a single amino acid replacement in NT‐3 (D15A). Both trkB‐L and trkB‐S transcripts were detected in embryonic neurons.

(R)-Profens are substrate-selective inhibitors of endocannabinoid oxygenation by COX-2

Scientific publishing developed as a way to communicate scientific discoveries to peers. By first simply collecting and later evaluating contributions, scientists were able to avoid duplicating the efforts of others and instead build directly on prior results. In the modern era, all journals make use of this same basic framework, but the ways in which papers are evaluated and the models of how papers are published vary widely. As each system has advantages and disadvantages, new models continue to arise to address real or perceived limitations of existing approaches. Within this context, we submit that journals coordinated by professional editors offer unique and important advantages to the scientific community. A professional editor acts as an in-house expert in and advocate for specific fields or subfields within the overall scientific scope of their journal. To improve their knowledge of ongoing efforts and challenges in their fields, and to promote communication within and across fields, editors attend conferences in their topic areas, engage with members of the community and commission reviews or other highlights of important work. Editors also take primary responsibility for submitted manuscripts in their fields, communicating with authors at all steps from an initial editorial decision through subsequent decisions on reviewed manuscripts and final acceptance through to publication of the paper. The initial assessment of a manuscript requires a careful evaluation of its merits in regards to the field as a whole, and occupies a significant proportion of an editor’s time. Whereas academic editors may consider a paper based on more first-hand knowledge of a specific subfield or experimental technique, professional editors are able to draw from a different set of information in making their decisions. For example, though professional editors are PhD-level scientists (usually with postdoctoral research experience or beyond) and thus have an appropriate scientific framework to understand and think critically about a manuscript’s contents, their position outside of a particular subfield affords a broader scientific perspective from which to evaluate the importance of any one result. This external but engaged view also permits a level of editorial independence that decouples an author’s track record or influence from the decision process. Additionally, because professional editors see a wide range of referee feedback and actively seek community guidance for establishing standards in a given field, they are well placed to recognize the type of discoveries likely to find support from external experts and the lines of evidence needed to support particular claims. By pursuing only those manuscripts that potentially offer unprecedented insights and contain appropriate experimental support, editors can provide timely feedback to the large majority of authors whose manuscripts are returned to them without review and focus their attention on manuscripts likely to be of greatest interest to the journal’s readership. Although we are sympathetic to authors’ frustrations that only a minority of papers are sent for peer review, we are perplexed by the occasional criticism that professional editors are unsuited to evaluate manuscripts. Indeed, ‘triaging’ papers is something that scientists do on a daily basis in selecting which articles in the literature they will read in full, in part or not at all. With the increasing volume of publications, even the use of Internet search engines and associated keyword-based alerts highlight more potentially relevant papers than can realistically be read by a single scientist. Professional editors thus effectively prescreen papers by acting not only as scientists but also as advocates of the scientific readership, considering papers in several dimensions in an effort to ensure that all papers published in the journal will be required reading for the field. How do we ‘screen’ papers? Contrary to suggestions that professional editors are indecisive and act merely as managers (Nature 472, 391, 2011), editors can only be effective if they form thoughtful opinions and act accordingly. Beyond the initial evaluation, in which editors must be able to enumerate the strengths of a particular manuscript, editors take an active role in managing the peer review process. As with academic editors, professional editors rely on referees to evaluate the technical merits of a manuscript, weigh in on whether the experimental evidence supports the major conclusions of a study and provide advice as to whether the findings are sufficient to merit publication in the journal (Nat. 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At Nature Chemical Biology, we continually challenge ourselves to keep connected with current research and be mindful of the evolution of the fields we cover. We strive to make our decisions timely and transparent for authors so that, even if they are unsuccessful with one submission, the insight they gain into our processes could benefit future submissions. Finally, we are aware that publishing models continually evolve (Nat. Chem. Biol. 2, 391, 2006), and we seek opportunities for improving the publishing process through the open dialogue we consistently pursue with our authors, referees and readers. ◾ Professional editors provide the perspective, consistency and responsiveness needed to identify and communicate groundbreaking scientific advances. Our professional opinion

Activation of the p75 Neurotrophin Receptor through Conformational Rearrangement of Disulphide-Linked Receptor Dimers

Ligand-mediated dimerization has emerged as a universal mechanism of growth factor receptor activation. Neurotrophins interact with dimers of the p75 neurotrophin receptor (p75(NTR)), but the mechanism of receptor activation has remained elusive. Here, we show that p75(NTR) forms disulphide-linked dimers independently of neurotrophin binding through the highly conserved Cys(257) in its transmembrane domain. Mutation of Cys(257) abolished neurotrophin-dependent receptor activity but did not affect downstream signaling by the p75(NTR)/NgR/Lingo-1 complex in response to MAG, indicating the existence of distinct, ligand-specific activation mechanisms for p75(NTR). FRET experiments revealed a close association of p75(NTR) intracellular domains that was transiently disrupted by conformational changes induced upon NGF binding. Although mutation of Cys(257) did not alter the oligomeric state of p75(NTR), the mutant receptor was no longer able to propagate conformational changes to the cytoplasmic domain upon ligand binding. We propose that neurotrophins activate p75(NTR) by a mechanism involving rearrangement of disulphide-linked receptor subunits.