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In brief: October 2008Signal transduction Structural coupling of SH2-kinase domains links Fes and Abl substrate recognition and kinase activation The Src-homology-2 (SH2) domain of Tyr kinases enhances activity, substrate recognition and oncogenicity of the linked catalytic domain. Yet the molecular mechanisms by which the SH2 domain can enhance catalytic activity and substrate recognition are poorly understood. The structure of the prototypic SH2-kinase unit of the human FES Tyr kinase now reveals that in its active conformation, the SH2 domain tightly interacts with the kinase N-terminal lobe and positions the kinase Vaccines Superior immunogenicity of inactivated whole virus H5N1 influenza vaccine is primarily controlled by Toll-like receptor signalling The ongoing threat of an influenza virus pandemic has propelled studies to improve the existing vaccines against this pathogen. This recent study helps to define what differentiates the robust immune response that is induced by an H5N1 influenza whole-virus vaccine from the response that is induced by the less-immunogenic split-virus or viral subunit vaccines. Stimulation of Toll-like receptors (TLRs) was important for the generation of protective adaptive immune responses, such as antibody production and a T-helper-1-cell response, to the H5N1 whole-virus vaccine. The finding that TLR7, which recognizes single-stranded RNA, was particularly important led the authors to suggest that intact viral nucleic acids that are present in whole-virus vaccines, but not in split-virus or viral subunit vaccines, were involved. In addition, these data strengthen the idea that the key to driving optimal adaptive immunity is through a vaccine that targets specific innate immune responses. HIV HIV envelope–CXCR4 signaling activities cofilin to overcome cortical actin restriction in resting CD4 T cells CXC-chemokine receptor 4 (CXCR4) is used by HIV to bind and fuse with host cells, but a role for this chemokine receptor during infection was unknown. This study now shows that latent infection of resting CD4+ T cells requires CXCR4-mediated signalling, which then induces changes in cortical actin. Dynamic reorganization of the actin cytoskeleton was necessary for migration of HIV to the nucleus and for viral replication, and inhibition of actin polymerization through the use of an F-actin-stabilizing agent decreased the probability of these events. Interestingly, HIV infection of resting CD4+ T cells, as well as treatment with beads coated with a CXCR4-specific antibody, induced the dephosphorylation of cofilin, which is involved in actin polymerization and depolymerization. Based on these observations, the authors conclude that HIV binding to CXCR4 triggers the dephosphorylation of cofilin, which promotes the actin dynamics that are required for viral latency. Natural killer T cells The transcription factor PLZF directs the effector program of the NKT cell lineage Using a microarray technique, the transcription factor PLZF (promyelocytic leukaemia zinc finger) was identified as a transcriptional signature of natural killer T (NKT) cells. This protein, which is related to the CD4+ T-cell-specifying factor Th-POK, was expressed early during NKT-cell development and was required for the intrathymic proliferation and acquisition of effector functions of these cells. Other immune-cell lineages, with the exception of mucosal-associated invariant T (MAIT) cells, were not found to express PLZF. Mice deficient for PLZF had marked irregularities in the number and tissue localization of NKT cells compared with wild-type mice, whereas transgenic expression of PLZF in CD4+ T cells induced an effector phenotype and homing pattern that resembled that of developing NKT cells. Therefore, PLZF is uniquely important for specifying the effector function of NKT cells and probably of the closely related MAIT-cell subset. Metastasis Seeding and propagation of untransformed mouse mammary cells in the lung The metastatic growth of tumour cells is often thought of as a late event in tumour progression. However, Harold Varmus and colleagues have found that mouse mammary epithelial cells that express tetracycline-regulated forms of MYC and oncogenic Kras can form lung metastases without having previously been part of a primary tumour. Specifically, the authors intravenously injected these cells into Rag1-null mice that had been fed doxycycline so that the oncogenes were only expressed once the cells were circulating within the mice. They found that these cells could form lung metastases. They confirmed and extended these results using cells that have regulated expression of polyoma middle T (PyMT) antigen. These cells could form small mammary foci and survive in the lungs for up to 16 weeks in the absence of PyMT expression. Moreover, induced expression of PyMT 1.5-16 weeks after injection resulted in the formation of metastases within the lungs. Therefore, oncogenic expression is only required to induce the rapid, metastatic growth of mammary epithelial cells residing in the lung and not for earlier stages of metastasis after intravasation. Oncogenes Kras regulatory elements and exon 4A determine mutation specificity in lung cancer The oncogenic capacity of the individual Ras genes seems to be tissue-type-dependent. To investigate why, Allan Balmain and colleagues used Kras4b and Hras knock-in (KI) mice. Importantly, both transgenes were knocked into the Kras locus, such that homozygous Hras KI mice express no KRAS. Surprisingly, the homozygous Hras KI mice developed ~10-fold more lung tumours than wild-type controls after treatment with the carcinogen urethane. Further investigation showed that the mutation of Hras was dependent on its expression from the Kras locus and that tissue-specific mutation preferences involve cis-acting regulatory elements specific to each gene rather than the functional properties of the proteins. Interestingly, they also found that KI mice expressing only Kras4b (the dominant KRAS isoform) were largely resistant to urethane-induced lung cancer. Further analyses indicate that the 4A isoform is important for lung carcinogenesis. However, KRAS4A has limited expression within the lung, although it is potentially expressed in lung stem cells. Further investigations are needed to understand the implications of these findings. Signalling Oncogenic MAPK signalling stimulates mTORC1 activity by promoting RSK-mediated raptor phosphorylation Raptor, a scaffolding protein, regulates substrate recruitment to mammalian target of rapamycin (mTOR) complex 1 (mTORC1). This paper shows that raptor is phosphorylated by p90 ribosomal S6 kinase 1 and 2 as a result of mitogen-activated protein kinase (MAPK) signalling. This finding suggests a mechanism through which MAPK-dependent signalling can activate mTORC1 in the absence of phosphoinositide 3-kinase-Akt activation, and has implications for resistance to rapamycin-based drugs. Development The NDR/LATS family kinase Cbk1 directly controls transcriptional asymmetry These authors have found a new mechanism by which mother and daughter cells acquire different fates in Saccharomyces cerevisiae. The distribution of the transcriptional regulator Ace2 changes from uniform to asymmetric during cell division owing to phosphorylation by the protein kinase Cbk1, which causes Ace2 to become trapped in the daughter nucleus and leads to different gene expression programmes in mother and daughter cells. Molecular neuroscience S-nitrosylation of histone deacetylase 2 induces chromatin remodelling in neurons The precise mechanisms through which neurotrophic factors influence gene expression to regulate growth and survival are largely unknown. In this study, a known mediator of brain-derived neurotrophic factor signalling in neurons, nitric oxide, was found to induce S-nitrosylation of histone deacetylase 2 (HDAC2). This modification reduced HDAC2's ability to associate with chromatin, thereby facilitating the acetylation of histones H3 and H4 and resulting in the expression of genes that regulate dendritic growth and branching. Addiction Cocaine regulates MEF2 to control synaptic and behavioral plasticity
Cocaine addiction results in behavioural changes and increased spine density on medium-sized spiny neurons in the nucleus accumbens. Here, cocaine increased spine density by reducing the activity of the transcription factor myocyte enhancer factor 2 (MEF2). Cocaine did not alter spine density in mice expressing a constitutively active form of MEF2; surprisingly, however, behavioural responses to cocaine were enhanced, suggesting that the increase in spine density is functionality uncoupled from behavioural responses. The identification of MEF2 as a key player in drug addiction could lead to novel treatments. Nuclear receptors Cytosporone B is an agonist for nuclear orphan receptor Nur77 The nuclear orphan receptor Nur77 has important roles in apoptosis and glucose homeostasis. This paper describes how cytosporone B, an octaketide isolated from fungi, is a naturally occurring agonist for Nur77 that stimulates transactivational activity towards target genes including Nr4a1 (Nur77) itself. In mice, the ligand enhanced gluconeogenesis and retarded xenograft tumour growth. So, cytosporone B could be used as a tool for understanding Nur77 function, and may represent a potential therapeutic compound for cancers and hypoglycaemia. Muscular disorders AMPK and PPARδ agonists are exercise mimetics As well as increasing athletic performance, exercise has beneficial effects in pathophysiological conditions including metabolic and muscle diseases. Narkar and colleagues found that a peroxisome proliferator-activated- Proteomics Mapping proteolytic events in apoptosis Current platforms for studying proteolysis have not generally allowed researchers to obtain a complete picture of the cleaved fragments of protease substrates on a large scale. Dix et al. now present an algorithm that integrates data from electrophoresis and quantitative liquid chromatography-tandem mass spectrometry analyses of fragment peptides into a 'peptograph', which plots a complete sequence map. They used this method to map caspase-mediated proteolytic events in apoptosis. Bioinformatics A NetPhorest of phosphorylation motifs Miller et al. present NetPhorest, a valuable database of protein phosphorylation consensus sequence motifs that are recognized by protein kinases and phosphorylation-dependent binding domains. This publicly available atlas (http://netphorest.info/) is fed by an automated data pipeline: these data are mapped to phylogenetic trees to derive linear motif models. | |
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C helix in an active configuration through essential packing and electrostatic interactions. This interaction is stabilized by ligand binding to the SH2 domain. Related findings with ABL kinase indicate an integrated SH2-kinase mechanism that is essential for effective signalling by these Tyr kinases.
(PPAR-