Hot off the presses! Dec 10 Cell

The Dec 10 issue of the Cell is now up on Pubget (About Cell): if you're at a subscribing institution, just click the link in the latest link at the home page. (Note you'll only be able to get all the PDFs in the issue if your institution subscribes to Pubget.)

Latest Articles Include:

• In This Issue
  - cell 143(6):849, 851 (2010)
  
• Select: Lipids Out Loud
  - cell 143(6):853, 855 (2010)
  If RNA ruled the last decade and DNA dominated the previous one, could the next decade be the one for lipids? The ultimate energy storage units, lipids are well known for encasing the cell in a watertight membrane, but lipids are oh-so much more. In particular, lipids are emerging as key signaling molecules in eukaryotes, transmitting messages both within and between cells. In this Select, we explore recent studies highlighting the diverse physiological roles of these "lipid messengers"—from modulating pain perception and bone formation to reining in renegade inflammatory responses.
• Insulin Signaling: Inositol Phosphates Get into the Akt
  - cell 143(6):861-863 (2010)
  An acute but transient response to insulin is essential for glucose homeostasis in mammals. Chakraborty et al. (2010) uncover a new feedback mechanism regulating insulin signaling. They show that the inositol pyrophosphate IP7, which is produced in response to insulin, inhibits the Akt kinase, a primary effector of insulin signaling.
• Consequences of mRNA Wardrobe Malfunctions
  - cell 143(6):863-865 (2010)
  As mRNAs are generated, they are clothed with proteins to form messenger ribonucleoprotein particles (mRNPs), which are then actively remodeled during various steps of gene expression. Franks et al. (2010) now show that mRNP remodeling is required even for the death of an mRNA.
• Kinases Charging to the Membrane
  - cell 143(6):865-867 (2010)
  Being at the right place and time is as fundamental to biology as it is to academic careers. In this issue, Moravcevic and colleagues (2010) survey membrane-interacting proteins in yeast and discover a new membrane-targeting module, the kinase associated-1 domain KA1, which ensures that proteins are active at the correct place and time.
• Exposing Contingency Plans for Kinase Networks
  - cell 143(6):867-869 (2010)
  Understanding how signaling pathways are interconnected is vital for characterizing mechanisms of normal development and disease pathogenesis. In this issue, Van Wageningen et al. (2010) examine phosphorylation networks in Sacharromyces cerevisiae with genome-wide expression profiling to identify recurring themes in signaling redundancy.
• Lipid Trafficking sans Vesicles: Where, Why, How?
  - cell 143(6):870-874 (2010)
  Eukaryotic cells possess a remarkable diversity of lipids, which distribute among cellular membranes by well-characterized vesicle trafficking pathways. However, transport of lipids by alternate, or "nonvesicular," routes is also critical for lipid synthesis, metabolism, and proper membrane partitioning. In the past few years, considerable progress has been made in characterizing the mechanisms of nonvesicular lipid transport and how it may go awry in particular diseases, but many fundamental questions remain for this rising field.
• Membrane Budding
  - cell 143(6):875-887 (2010)
  Membrane budding is a key step in vesicular transport, multivesicular body biogenesis, and enveloped virus release. These events range from those that are primarily protein driven, such as the formation of coated vesicles, to those that are primarily lipid driven, such as microdomain-dependent biogenesis of multivesicular bodies. Other types of budding reside in the middle of this spectrum, including caveolae biogenesis, HIV-1 budding, and ESCRT-catalyzed multivesicular body formation. Some of these latter events involve budding away from cytosol, and this unusual topology involves unique mechanisms. This Review discusses progress toward understanding the structural and energetic bases of these different membrane-budding paradigms.
• Lipidomics: New Tools and Applications
  - cell 143(6):888-895 (2010)
  Once viewed simply as a reservoir for carbon storage, lipids are no longer cast as bystanders in the drama of biological systems. The emerging field of lipidomics is driven by technology, most notably mass spectrometry, but also by complementary approaches for the detection and characterization of lipids and their biosynthetic enzymes in living cells. The development of these integrated tools promises to greatly advance our understanding of the diverse biological roles of lipids.
• Inositol Pyrophosphates Inhibit Akt Signaling, Thereby Regulating Insulin Sensitivity and Weight Gain
  - cell 143(6):897-910 (2010)
  The inositol pyrophosphate IP7 (5-diphosphoinositolpentakisphosphate), formed by a family of three inositol hexakisphosphate kinases (IP6Ks), modulates diverse cellular activities. We now report that IP7 is a physiologic inhibitor of Akt, a serine/threonine kinase that regulates glucose homeostasis and protein translation, respectively, via the GSK3β and mTOR pathways. Thus, Akt and mTOR signaling are dramatically augmented and GSK3β signaling reduced in skeletal muscle, white adipose tissue, and liver of mice with targeted deletion of IP6K1. IP7 affects this pathway by potently inhibiting the PDK1 phosphorylation of Akt, preventing its activation and thereby affecting insulin signaling. IP6K1 knockout mice manifest insulin sensitivity and are resistant to obesity elicited by high-fat diet or aging. Inhibition of IP6K1 may afford a therapeutic approach to obesity and diabetes.
• Loss of Anion Transport without Increased Sodium Absorption Characterizes Newborn Porcine Cystic Fibrosis Airway Epithelia
  - cell 143(6):911-923 (2010)
  Defective transepithelial electrolyte transport is thought to initiate cystic fibrosis (CF) lung disease. Yet, how loss of CFTR affects electrolyte transport remains uncertain. CFTR−/− pigs spontaneously develop lung disease resembling human CF. At birth, their airways exhibit a bacterial host defense defect, but are not inflamed. Therefore, we studied ion transport in newborn nasal and tracheal/bronchial epithelia in tissues, cultures, and in vivo. CFTR−/− epithelia showed markedly reduced Cl- and HCO3- transport. However, in contrast to a widely held view, lack of CFTR did not increase transepithelial Na+ or liquid absorption or reduce periciliary liquid depth. Like human CF, CFTR−/− pigs showed increased amiloride-sensitive voltage and current, but lack of apical Cl- conductance caused the change, not increased Na+ transport. These results indicate that CFTR provides the predominant transcellular pathway for Cl- and HCO3- in porcine airway epithelia, and reduced anion permeability may initiate CF airway disease.
• Sister Cohesion and Structural Axis Components Mediate Homolog Bias of Meiotic Recombination
  - cell 143(6):924-937 (2010)
  Meiotic double-strand break (DSB)-initiated recombination must occur between homologous maternal and paternal chromosomes ("homolog bias"), even though sister chromatids are present. Through physical recombination analyses, we show that sister cohesion, normally mediated by meiotic cohesin Rec8, promotes "sister bias"; that meiosis-specific axis components Red1/Mek1kinase counteract this effect, thereby satisfying an essential precondition for homolog bias; and that other components, probably recombinosome-related, directly ensure homolog partner selection. Later, Rec8 acts positively to ensure maintenance of bias. These complexities mirror opposing dictates for global sister cohesion versus local separation and differentiation of sisters at recombination sites. Our findings support DSB formation within axis-tethered recombinosomes containing both sisters and ensuing programmed sequential release of "first" and "second" DSB ends. First-end release would create a homology-searching "tentacle." Rec8 and Red1/Mek1 also independently license recombinational progression and abundantly localize to different domains. These domains could comprise complementary environments that integrate inputs from DSB repair and mitotic chromosome morphogenesis into the complete meiotic program.
• Upf1 ATPase-Dependent mRNP Disassembly Is Required for Completion of Nonsense- Mediated mRNA Decay
  - cell 143(6):938-950 (2010)
  Cellular mRNAs exist in messenger ribonucleoprotein (mRNP) complexes, which undergo transitions during the lifetime of the mRNAs and direct posttranscriptional gene regulation. A final posttranscriptional step in gene expression is the turnover of the mRNP, which involves degradation of the mRNA and recycling of associated proteins. How tightly associated protein components are released from degrading mRNPs is unknown. Here, we demonstrate that the ATPase activity of the RNA helicase Upf1 allows disassembly of mRNPs undergoing nonsense-mediated mRNA decay (NMD). In the absence of Upf1 ATPase activity, partially degraded NMD mRNA intermediates accumulate in complex with NMD factors and concentrate in processing bodies. Thus, disassembly and completion of turnover of mRNPs undergoing NMD requires ATP hydrolysis by Upf1. This uncovers a previously unappreciated and potentially regulated step in mRNA decay and raises the question of how other mRNA decay pathways release pro tein components of substrate mRNPs. PaperFlick To view the video inline, enable JavaScript on your browser. However, you can download and view the video by clicking on the icon below Download this Video (28148 K)
• Dynamics of Cullin-RING Ubiquitin Ligase Network Revealed by Systematic Quantitative Proteomics
  - cell 143(6):951-965 (2010)
  Dynamic reorganization of signaling systems frequently accompanies pathway perturbations, yet quantitative studies of network remodeling by pathway stimuli are lacking. Here, we report the development of a quantitative proteomics platform centered on multiplex absolute quantification (AQUA) technology to elucidate the architecture of the cullin-RING ubiquitin ligase (CRL) network and to evaluate current models of dynamic CRL remodeling. Current models suggest that CRL complexes are controlled by cycles of CRL deneddylation and CAND1 binding. Contrary to expectations, acute CRL inhibition with MLN4924, an inhibitor of the NEDD8-activating enzyme, does not result in a global reorganization of the CRL network. Examination of CRL complex stoichiometry reveals that, independent of cullin neddylation, a large fraction of cullins are assembled with adaptor modules, whereas only a small fraction are associated with CAND1. These studies suggest an alternative model of CRL dynami city where the abundance of adaptor modules, rather than cycles of neddylation and CAND1 binding, drives CRL network organization.
• Kinase Associated-1 Domains Drive MARK/PAR1 Kinases to Membrane Targets by Binding Acidic Phospholipids
  - cell 143(6):966-977 (2010)
  Phospholipid-binding modules such as PH, C1, and C2 domains play crucial roles in location-dependent regulation of many protein kinases. Here, we identify the KA1 domain (kinase associated-1 domain), found at the C terminus of yeast septin-associated kinases (Kcc4p, Gin4p, and Hsl1p) and human MARK/PAR1 kinases, as a membrane association domain that binds acidic phospholipids. Membrane localization of isolated KA1 domains depends on phosphatidylserine. Using X-ray crystallography, we identified a structurally conserved binding site for anionic phospholipids in KA1 domains from Kcc4p and MARK1. Mutating this site impairs membrane association of both KA1 domains and intact proteins and reveals the importance of phosphatidylserine for bud neck localization of yeast Kcc4p. Our data suggest that KA1 domains contribute to "coincidence detection," allowing kinases to bind other regulators (such as septins) only at the membrane surface. These findings have important implica tions for understanding MARK/PAR1 kinases, which are implicated in Alzheimer's disease, cancer, and autism. PaperClip To listen to this audio, enable JavaScript on your browser. However, you can download and play the audio by clicking on the icon below Download this Audio (3657 K)
• The Fused/Smurf Complex Controls the Fate of Drosophila Germline Stem Cells by Generating a Gradient BMP Response
  - cell 143(6):978-990 (2010)
  In the Drosophila ovary, germline stem cells (GSCs) are maintained primarily by bone morphogenetic protein (BMP) ligands produced by the stromal cells of the niche. This signaling represses GSC differentiation by blocking the transcription of the differentiation factor Bam. Remarkably, bam transcription begins only one cell diameter away from the GSC in the daughter cystoblasts (CBs). How this steep gradient of response to BMP signaling is formed has been unclear. Here, we show that Fused (Fu), a serine/threonine kinase that regulates Hedgehog, functions in concert with the E3 ligase Smurf to regulate ubiquitination and proteolysis of the BMP receptor Thickveins in CBs. This regulation generates a steep gradient of BMP activity between GSCs and CBs, allowing for bam expression on CBs and concomitant differentiation. We observed similar roles for Fu during embryonic development in zebrafish and in human cell culture, implying broad conservation of this mechanism.
• Functional Overlap and Regulatory Links Shape Genetic Interactions between Signaling Pathways
  - cell 143(6):991-1004 (2010)
  To understand relationships between phosphorylation-based signaling pathways, we analyzed 150 deletion mutants of protein kinases and phosphatases in S. cerevisiae using DNA microarrays. Downstream changes in gene expression were treated as a phenotypic readout. Double mutants with synthetic genetic interactions were included to investigate genetic buffering relationships such as redundancy. Three types of genetic buffering relationships are identified: mixed epistasis, complete redundancy, and quantitative redundancy. In mixed epistasis, the most common buffering relationship, different gene sets respond in different epistatic ways. Mixed epistasis arises from pairs of regulators that have only partial overlap in function and that are coupled by additional regulatory links such as repression of one by the other. Such regulatory modules confer the ability to control different combinations of processes depending on condition or context. These properties likely contribute to the evolutionary maintenance of paralogs and indicate a way in which signaling pathways connect for multiprocess control.
• An Integrated Approach to Uncover Drivers of Cancer
  - cell 143(6):1005-1017 (2010)
  Systematic characterization of cancer genomes has revealed a staggering number of diverse aberrations that differ among individuals, such that the functional importance and physiological impact of most tumor genetic alterations remain poorly defined. We developed a computational framework that integrates chromosomal copy number and gene expression data for detecting aberrations that promote cancer progression. We demonstrate the utility of this framework using a melanoma data set. Our analysis correctly identified known drivers of melanoma and predicted multiple tumor dependencies. Two dependencies, TBC1D16 and RAB27A, confirmed empirically, suggest that abnormal regulation of protein trafficking contributes to proliferation in melanoma. Together, these results demonstrate the ability of integrative Bayesian approaches to identify candidate drivers with biological, and possibly therapeutic, importance in cancer.
• Comprehensive Polyadenylation Site Maps in Yeast and Human Reveal Pervasive Alternative Polyadenylation
  - cell 143(6):1018-1029 (2010)
  The emerging discoveries on the link between polyadenylation and disease states underline the need to fully characterize genome-wide polyadenylation states. Here, we report comprehensive maps of global polyadenylation events in human and yeast generated using refinements to the Direct RNA Sequencing technology. This direct approach provides a quantitative view of genome-wide polyadenylation states in a strand-specific manner and requires only attomole RNA quantities. The polyadenylation profiles revealed an abundance of unannotated polyadenylation sites, alternative polyadenylation patterns, and regulatory element-associated poly(A)+ RNAs. We observed differences in sequence composition surrounding canonical and noncanonical human polyadenylation sites, suggesting novel noncoding RNA-specific polyadenylation mechanisms in humans. Furthermore, we observed the correlation level between sense and antisense transcripts to depend on gene expression levels, supporting the vie w that overlapping transcription from opposite strands may play a regulatory role. Our data provide a comprehensive view of the polyadenylation state and overlapping transcription.
• SnapShot: Inositol Phosphates
  - cell 143(6):1030-1030.e1 (2010)