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Introducing PaperClips Comment on a Cell Article All articles in this issue are open for comment. We welcome your thoughts and constructive feedback on the work we publish and are eager to provide a more interactive mechanism between authors and readers for valuable scientific discussions. Comments are reviewed by the Cell editors prior to posting. Featured Article Rewiring the Specificity of Two-Component Signal Transduction Systems Understanding how cells coordinate the activity of multiple signaling pathways to prevent unwanted crosstalk remains a challenge. Skerker et al. address this question in the context of two-component signal transduction systems in bacteria. Using computational analysis of amino acid coevolution in cognate kinase-substrate pairs, the authors identify putative specificity residues. They then demonstrate that a subset of the coevolving residues is sufficient, when mutated, to switch the specificity of a histidine kinase. These results suggest that analyses of coevolution may help guide the redesign of other protein-protein interactions. |
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| Table of Contents for Cell, Volume 133, Issue 3. June 13, 2008 |
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Essay Previews Rewiring Bacteria, Two Components at a Time From ER to Eph Receptors: New Roles for VAP Fragments Golgi Governance: The Third Way The Platypus Genome Unraveled Minireview Snapshot Articles A point mutation in the protein VAPB is associated with Amyotrophic Lateral Sclerosis (ALS) in humans. Tsuda et al. now show that one of the domains of the VAP protein, the MSP domain, is cleaved and secreted to act as a ligand for Eph receptors. In flies, the VAP33 mutation corresponding to that found in ALS patients leads to a failure to secrete the VAP MSP domain, as well as the accumulation of ubiquitinated VAP33 in endoplasmic reticulum inclusions. This work identifies VAP MSP domains as secreted ligands for Eph receptors and provides insight into mechanisms that may impact the pathogenesis of ALS. A Redox-Dependent Pathway for Regulating Class II HDACs and Cardiac Hypertrophy Ago et al. identify a mechanism by which antioxidant thioredoxin1 (Trx1) facilitates the reduction of signaling molecules by cysteine thiol-disulfide exchange to attenuate cardiac hypertrophy. Class II histone deacetylases (HDACs) are known negative regulators of cardiac hypertrophy, but hypertrophic stimuli can induce disulfide bond formation in HDAC4 to facilitate its inactivation by nuclear export. Trx1 inhibits this nuclear export by reducing HDAC4 cysteine residues. The study reveals a regulatory mechanism of cardiac hypertrophy in which the nucleo-cytoplasmic shuttling of class II HDACs is modulated by Trx1-mediated redox regulation. Systemic Endocrine Instigation of Indolent Tumor Growth Requires Osteopontin The recurrence of cancer in the form of metastatic disease causes approximately 90% of cancer deaths. McAllister et al. report that human breast carcinomas can facilitate the growth of otherwise-indolent tumor cells located at distant anatomical sites. This action-at-a-distance tumor induction is accomplished when the instigating tumors release signals, including the protein osteopontin, that activate the bone marrow to deliver cells to the responding tumors, thereby facilitating their outgrowth. These results demonstrate that outgrowth of indolent tumor cells can be governed on a systemic level by endocrine factors. Chemokine Signaling via the CXCR2 Receptor Reinforces Senescence Oncogene-Induced Senescence Relayed by an Interleukin-Dependent Inflammatory Network Senescence, an important anticancer response, is an irreversible growth arrest triggered by cellular stresses such as telomere erosion, DNA damage, or oncogene signaling. Two groups now report that secreted cytokines and their receptors, usually involved in the stimulation of proliferation, play an unexpected role in senescence. In the first paper, Acosta et al. identify the chemokine receptor CXCR2/IL8RB and found its expression upregulated during senescence and in preneoplastic lesions, whereas an inactive CXCR2 mutant allele was detected in tumors. In the second paper, Kuilman et al. report that interleukin-6 (IL-6) is required for oncogene-induced senescence in a cell-autonomous manner. Together the papers suggest that cytokines have an autocrine role in the inhibition of cell proliferation in addition to their paracrine function in stimulating proliferation. Centrosome Amplification Can Initiate Tumorigenesis in Flies Centrosome amplification is a common feature of many human tumors. In this issue, Basto et al. have investigated the consequences of centrosome amplification in the fruit fly Drosophila melanogaster. Surprisingly, they found that the presence of extra centrosomes in fly somatic cells does not generate high levels of chromosome instability. However, the asymmetric division of larval neural stem cells (neuroblasts) is compromised, and transplantation of larval neuroblasts with extra centrosomes into wild-type hosts induces overproliferation of the cells and metastatic tumor formation. These results suggest that centrosome amplification can initiate tumor formation. Rewiring the Specificity of Two-Component Signal Transduction Systems Understanding how cells coordinate the activity of multiple signaling pathways to prevent unwanted crosstalk remains a challenge. Skerker et al. address this question in the context of two-component signal transduction systems in bacteria. Using computational analysis of amino acid coevolution in cognate kinase-substrate pairs, the authors identify putative specificity residues. They then demonstrate that a subset of the coevolving residues is sufficient, when mutated, to switch the specificity of a histidine kinase. These results suggest that analyses of coevolution may help guide the redesign of other protein-protein interactions. Transport through the Golgi Apparatus by Rapid Partitioning within a Two-Phase Membrane System The Golgi apparatus is typically composed of several flattened cisternae that process and sort newly synthesized proteins and lipids moving through the secretory pathway. One model for how the Golgi accomplishes these tasks is cisternal maturation, in which the cargo remains within a given cisterna as it passes, conveyor-belt-like, through the stacks. This model predicts that newly arrived cargo moving through the Golgi would have a lag time prior to exiting the Golgi. By monitoring the flux of cargo through the Golgi, Patterson et al. instead find that cargo exits from partitioned Golgi domains at an exponential rate. Using simulations, the authors construct a new model for intra-Golgi transport that involves rapid partitioning of enzymes and transmembrane cargo between two lipid phases across the cisternae. Structural Basis for the Cooperation of Hsp70 and Hsp110 Chaperones in Protein Folding Hsp70 chaperones mediate protein folding, transport, and conformational reorganization by an ATP-dependent mechanism. In eukaryotic cells, Hsp70 functions are regulated by the nucleotide exchange factors called Hsp110 that form transient complexes with Hsp70 proteins. In this issue, Polier et al. present functional characterization and the X-ray crystal structure of the Hsp110/Hsp70 complex. These results support a model for Hsp70 regulation in contrast to the previously characterized allosteric control of Hsp70 function. Instead, Hsp110 interacts with Hsp70 at its nucleotide-binding site to modulate its structure. This interaction tunes Hsp70 nucleotide affinity and catalyzes the dissociation of ADP from Hsp70, a process that accelerates protein release to promote folding. BAP31 Interacts with Sec61 Translocons and Promotes Retrotranslocation of CFTRΔF508 via the Derlin-1 Complex Newly-synthesized membrane proteins integrate into the endoplasmic reticulum (ER) membrane as they emerge from the Sec61 translocon. The fate of these proteins depends on other ER complexes that control their egress, retention, or degradation. Employing an unstable CFTR mutant as a model protein, Wang et al. now show that the resident ER membrane protein BAP31 escorts newly synthesized mutant CFTR from the translocon to the Derlin-1 complex and promotes its extraction from the ER for degradation in the cytoplasm. Thus, BAP31 serves a direct role in delivering newly synthesized proteins to Derlin-1 for retrotranslocation, thereby linking the biosynthetic and degradative pathways in the ER. Asymmetric Homotypic Interactions of the Atypical Cadherin Flamingo Mediate Intercellular Polarity Signaling Many epithelial cells become polarized within the plane of the epithelium, and this "planar cell polarity" is important for a variety of developmental events. A key but poorly understood step in determining cell polarity is the communication and coordination of polarity information between neighboring cells. Here Chen et al. show that the atypical cadherin, Flamingo, transmits signals between adjacent cells. Flamingo forms homodimers with surprising asymmetric function that produce unequal responses in neighboring cells, thereby allowing cells to align their polarity with one another. Resource Many transcription factors are known to regulate gene expression and thus pluripotency in embryonic stem (ES) cells. To gain further insight into this transcription regulatory network, Chen et al. identified the binding sites of 13 transcription factors in ES cells throughout the genome. The authors uncovered two classes of hotspots in the genome that are occupied by multiple transcription factors. These sites are associated with genes specifically expressed in undifferentiated cells. The LIF and Bmp signaling pathways, which are required to maintain pluripotency, tend to converge with the Nanog/Oct4/Sox2 class I hotspot through the transcriptional effectors STAT3 and Smad1. The resulting network will be useful for uncovering new regulators of self-renewal, pluripotency, and reprogramming.
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