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The Babraham Institute Publications database contains details of all publications resulting from our research groups and scientific facilities. Pre-prints by Institute authors can be viewed on the Institute's bioRxiv channel. We believe that free and open access to the outputs of publicly‐funded research offers significant social and economic benefits, as well as aiding the development of new research. We are working to provide Open Access to as many publications as possible and these can be identified below by the padlock icon. Where this hasn't been possible, subscriptions may be required to view the full text.
 

S Higashi, S Biskup, AB West, D Trinkaus, VL Dawson, RL Faull, HJ Waldvogel, H Arai, TM Dawson, DJ Moore, PC Emson

Mutations in the LRRK2 gene cause autosomal dominant, late-onset parkinsonism, which presents with pleomorphic pathology including alpha-synucleopathy. To promote our understanding of the biological role of LRRK2 in the brain we examined the distribution of LRRK2 mRNA and protein in postmortem human brain tissue from normal and neuropathological subjects. In situ hybridization and immunohistochemical analysis demonstrate the expression and localization of LRRK2 to various neuronal populations in brain regions implicated in Parkinson's disease (PD) including the cerebral cortex, caudate-putamen and substantia nigra pars compacta. Immunofluorescent double labeling studies additionally reveal the prominent localization of LRRK2 to cholinergic-, calretinin- and GABA(B) receptor 1-positive, dopamine-innervated, neuronal subtypes in the caudate-putamen. The distribution of LRRK2 in brain tissue from sporadic PD and dementia with Lewy bodies (DLB) subjects was also examined. In PD brains, LRRK2 immunoreactivity localized to nigral neuronal processes is dramatically reduced which reflects the disease-associated loss of dopaminergic neurons in this region. However, surviving nigral neurons occasionally exhibit LRRK2 immunostaining of the halo structure of Lewy bodies. Moreover, LRRK2 immunoreactivity is not associated with Lewy neurites or with cortical Lewy bodies in sporadic PD and DLB brains. These observations indicate that LRRK2 is not a primary component of Lewy bodies and does not co-localize with mature fibrillar alpha-synuclein to a significant extent. The localization of LRRK2 to key neuronal populations throughout the nigrostriatal dopaminergic pathway is consistent with the involvement of LRRK2 in the molecular pathogenesis of familial and sporadic parkinsonism.

+view abstract Brain research, PMID: 17512502 2007

CR Quilter, SC Blott, AE Wilson, MR Bagga, CA Sargent, GL Oliver, OI Southwood, CL Gilbert, A Mileham, NA Affara

Childbirth is a period of substantial rapid biological and psychological change and a wide range of psychotic disorders can occur ranging from mild 'baby blues' to severe episodes of psychotic illnesses. Puerperal psychosis is the most extreme form of postnatal psychosis, occurring in 1 in 1,000 births. In this study, we have used the pig as an animal model for human postnatal psychiatric illness. Our aim was to identify quantitative trait loci (QTL) associated with maternal (infanticide) sow aggression. This is defined by sows attacking and killing their own newborn offspring, within 24 hr of birth. An affected sib pair whole genome linkage analysis was carried out with 80 microsatellite markers covering the 18 porcine autosomes and the X chromosome, with the aim of identifying chromosomal regions responsible for this abnormal behavior. Analysis was carried out using the non-parametric linkage test of Whittemore and Halpern, as implemented in the Merlin software. The results identified 4 QTL mapping on Sus scrofa chromosomes 2 (SSC2), 10 (SSC10), and X (SSCX). The peak regions of these QTL are syntenic to HSA 5q14.3-15, 1q32, Xpter-Xp2.1, and Xq2.4-Xqter, respectively. Several potential candidate genes lie in these regions in addition to relevant abnormal behavioral QTL, found in humans and rodents.

+view abstract American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics, PMID: 17503476 2007

A Saudemont, A Hamrouni, P Marchetti, J Liu, N Jouy, D Hetuin, F Colucci, B Quesnel

In the BCR/ABL DA1-3b mouse model of acute myelogenous leukemia, dormant tumor cells may persist in the host in a state of equilibrium with the CD8(+) CTL-mediated immune response by actively inhibiting T cells. Dormant tumor cells also show a progressive decrease of suppressor of cytokine signaling 1 (SOCS1) gene expression and a deregulation of the Janus-activated kinase/signal transducers and activators of transcription (JAK/STAT) pathway due to methylation of the SOCS1 gene. Dormant tumor cells were more resistant to apoptosis induced by specific CTLs, but resistance decreased when SOCS1 expression was restored via demethylation or gene transfer. AG490 JAK2 inhibitor decreased the resistance of dormant tumor cells to CTLs, but MG132 proteasome inhibitor was effective only in SOCS1-transfected cells. Thus, SOCS1 regulation of the JAK/STAT pathways contributes to the resistance of tumor cells to CTL-mediated killing. Resistance of dormant tumor cells to apoptosis was also observed when induced by irradiation, cytarabine, or imatinib mesylate, but was reduced by SOCS1 gene transfer. This cross-resistance to apoptosis was induced by interleukin 3 (IL-3) overproduction by dormant tumor cells and was reversed with an anti-IL-3 antibody. Thus, tumor cells that remain dormant for long periods in the host in spite of a specific CTL immune response may deregulate their JAK/STAT pathways and develop cross-resistance to various treatments through an IL-3 autocrine loop. These data suggest possible new therapeutic targets to eradicate dormant tumor cells.

+view abstract Cancer research, PMID: 17483365 2007

D Gaboriau, EA Howes, J Clark, R Jones

Specific binding of spermatozoa to the zona pellucida that surrounds mammalian eggs is a key step in the fertilization process. However, the sperm proteins that recognise zona pellucida receptors remain contentious despite longstanding research efforts to identify them. Here we present evidence that proacrosin, a tissue-specific protein found within the acrosomal vesicle of all mammalian spermatozoa, is a multifunctional protein that mediates binding of acrosome-reacted spermatozoa to zona glycoproteins via a stereospecific polysulfate recognition mechanism. Using sulfated versus non-sulfated forms of chemically defined compounds in binding assays employing native proteins in their normal cellular location or conjugated to FluoSpheres, we have attempted to identify the sulfation "code" required for recognition. Results show that protein conformation is important for specificity and that at least 2 sulfate groups are required to cross-link spatially separated docking sites on proacrosin. The consistently most effective inhibitory compounds were suramin and quercetin-3beta-d-glucoside sulfate. The results support our hypothesis that proacrosin is one of several proteins in the acrosomal matrix that retain acrosome reacted spermatozoa on the zona surface prior to penetration. They also establish, as a proof-of-principle, the feasibility of synthesising sulfated compounds of high specificity as antifertility agents for human or animal use.

+view abstract Developmental biology, PMID: 17482590 2007

FM Marelli-Berg, K Okkenhaug, V Mirenda Immunology

T-cell-receptor triggering and the delivery of co-stimulation are essential events leading to T cell expansion, differentiation and effector function. The influence that such signals exert on T cell migration during and following priming has been highlighted by recent reports. Moreover, induction of peripheral tolerance might act in part by affecting T cell migration. Here, we propose that the integration of co-stimulatory signals, which regulate the ability of primed T cells to access nonlymphoid tissue, and cognate recognition of the endothelium, which determines the selective recruitment of specific T cells, contribute to the anatomy of T cell-mediated immunity and tolerance. The implications for therapeutic strategies manipulating these signals are discussed.

+view abstract Trends in immunology, PMID: 17481953 2007

A Rodriguez, E Vigorito, S Clare, MV Warren, P Couttet, DR Soond, S van Dongen, RJ Grocock, PP Das, EA Miska, D Vetrie, K Okkenhaug, AJ Enright, G Dougan, M Turner, A Bradley Immunology

MicroRNAs are a class of small RNAs that are increasingly being recognized as important regulators of gene expression. Although hundreds of microRNAs are present in the mammalian genome, genetic studies addressing their physiological roles are at an early stage. We have shown that mice deficient for bic/microRNA-155 are immunodeficient and display increased lung airway remodeling. We demonstrate a requirement of bic/microRNA-155 for the function of B and T lymphocytes and dendritic cells. Transcriptome analysis of bic/microRNA-155-deficient CD4+ T cells identified a wide spectrum of microRNA-155-regulated genes, including cytokines, chemokines, and transcription factors. Our work suggests that bic/microRNA-155 plays a key role in the homeostasis and function of the immune system.

+view abstract Science (New York, N.Y.), PMID: 17463290 2007

AV Probst, F Santos, W Reik, G Almouzni, W Dean Epigenetics

In mammals, paternal and maternal pronuclei undergo profound chromatin reorganisation upon fertilisation. How these events are orchestrated within centromeric regions to ensure proper chromosome segregation in the following cellular divisions is unknown. In this study, we followed the dynamic unfolding of the centromeric regions, i.e. the centric and pericentric satellite repeats, by DNA fluorescent in situ hybridization (FISH) during the first cell cycle up to the two-cell stage. The distinct chromatin from female and male gametes both undergo rapid remodelling and reach a zygotic organisation in which the satellites occupy restricted spatial domains surrounding the nucleolar precursor body. A transition from this zygotic to a somatic cell-like organisation takes place during the two-cell stage. Using 3D immuno-FISH, we find that, whereas maternal pericentric regions are marked with H3K9me3, H4K20me3 and HP1beta, paternal ones only showed HP1beta marking. Thus, despite different chromatin features, male and female pronuclei organise their centromeric regions in the same way within the nuclei to align chromosomes on the metaphase plate and segregate them appropriately. Our findings highlight the importance of ensuring a proper centromere function while preserving the distinction of parental genome origin during the return to totipotency in the zygote.

+view abstract Chromosoma, PMID: 17447080 2007

RE Colebrooke, PM Chan, PJ Lynch, K Mooslehner, PC Emson

The vesicular monoamine transporter type 2 (VMAT2) packages pre-synaptic monoamines into vesicles. Previously, we generated mice hypomorphic for the VMAT2 gene (Slc18a2), which results in a approximately 95% reduction in VMAT2 protein, disrupted vesicular storage, severe depletion of striatal dopamine and mice with moderate motor behaviour deficits. Dopamine released from mid-brain dopamine neurons acts on post-synaptic type 1 (D1) and 2 (D2) receptors located on striatal medium spiny neurons to initiate a signalling cascade that leads to altered transcription factor activity, gene expression and neuronal activity. We investigated striatal gene expression changes in VMAT2hypo mice by quantitative real-time PCR and in situ hybridisation. Despite unaltered expression of D1 and D2 dopamine receptors, there were dramatic alterations in striatal mRNAs encoding the neuropeptides substance P, dynorphin, enkephalin and cholecystokinin. The promoters of these genes are regulated by a combination of transcription factors that includes cAMP responsive element binding protein-1 (CREB) and c-Fos. Indeed, the changes in peptide mRNAs were associated with elevated expression of Creb1 and c-Fos. These data indicate that striatal dopamine depletion, as a consequence of deficient vesicular storage in this mouse, triggers a complex program of gene expression, consistent with this mouse being an excellent model of Parkinson's disease.

+view abstract Brain research, PMID: 17433807 2007

B Stockinger, M Veldhoen Immunology

IL-17-producing T cells have recently been classified as a new effector T-cell subset, termed Th17, which is distinct from Th1, Th2 and Treg subsets. There has been much progress in the past year, leading to identification of the molecular mechanisms that drive differentiation of Th17 T cells. This has helped to clarify many aspects of their role in host defense as well as in autoimmunity. Nevertheless, many intriguing questions remain to be answered regarding the regulation of Th17-mediated responses as well as their interactions with the other T-cell subsets. Furthermore, the role of pathogens and pathogen-derived molecules in influencing effector T-cell polarization needs to be re-evaluated in the light of the differentiation conditions that favor Th17 T-cell responses.

+view abstract Current opinion in immunology, PMID: 17433650 2007

E Galkina, O Florey, A Zarbock, BR Smith, G Preece, MB Lawrence, DO Haskard, A Ager Signalling

L-selectin mediates tethering and rolling of lymphocytes in high endothelial venules (HEV) of lymph nodes (LN) and of leukocytes at inflammatory sites. We used transgenic mice expressing varying levels of wild-type or a non-cleavable mutant form of L-selectin on T cells to determine the relationship between L-selectin density, tethering and rolling, and migration into LN. T cells expressing supraphysiological levels of either wild-type or non-cleavable L-selectin showed rolling parameters similar to C57BL/6 T cells in hydrodynamic flow assays and during rolling in Peyer's patch HEV. In contrast, PMA- or antigen-activated T cells and L-selectin(+/-) T cells expressing subphysiological levels of L-selectin showed reduced numbers of rolling cells with increased rolling velocity. Short-term homing studies showed that elevated expression of L-selectin above physiological levels had no effect on T cell migration to LN; however, low L-selectin expression resulted in reduced T cell homing to LN. Thus, T lymphocyte migration into LN is regulated by the density of cell surface L-selectin. In addition, there is a saturable density of L-selectin required for optimal homing to PLN in C57BL/6 mice, the L-selectin level on circulating naive T cells promotes optimal homing, and increased expression above saturating levels promotes no further increase in T cell recruitment.

+view abstract European journal of immunology, PMID: 17429841 2007

S Duquerroy, EA Stura, S Bressanelli, SM Fabiane, MC Vaney, D Beale, M Hamon, P Casali, FA Rey, BJ Sutton, MJ Taussig

Rheumatoid factors (RF) are autoantibodies that recognize epitopes in the Fc region of immunoglobulin (Ig) G and that correlate with the clinical severity of rheumatoid arthritis (RA). Here we report the X-ray crystallographic structure, at 3 A resolution, of a complex between the Fc region of human IgG1 and the Fab fragment of a monoclonal IgM RF (RF61), derived from an RA patient and with a relatively high affinity for IgG Fc. In the complex, two Fab fragments bind to each Fc at epitopes close to the C terminus, and each epitope comprises residues from both Cgamma3 domains. A central role in the unusually hydrophilic epitope is played by the side-chain of Arg355, accounting for the subclass specificity of RF61, which recognizes IgG1,-2, and -3 in preference to IgG4, in which the corresponding residue is Gln355. Compared with a previously determined complex of a lower affinity RF (RF-AN) bound to IgG4 Fc, in which only residues at the very edge of the antibody combining site were involved in binding, the epitope bound by RF61 is centered in classic fashion on the axis of the V(H):V(L) beta-barrel. The complementarity determining region-H3 loop plays a key role, forming a pocket in which Arg355 is bound by two salt-bridges. The antibody contacts also involve two somatically mutated V(H) residues, reinforcing the suggestion of a process of antigen-driven maturation and selection for IgG Fc during the generation of this RF autoantibody.

+view abstract Journal of molecular biology, PMID: 17395205 2007

Liston A, Siggs OM, Goodnow CC Immunology

Genetic variants of interleukin 2 (IL-2) and its receptor are associated with murine and human susceptibility to Type 1 diabetes, yet the role of IL-2 in controlling pancreatic islet-reactive T cells is unknown. Here, we develop a model where IL-2 deficiency precipitates a breakdown of self-tolerance and progression to diabetes, and its action upon diabetogenic islet-specific CD4 T cells can be tracked. We find that IL-2 is not required for Aire-dependent thymic clonal deletion of high-avidity diabetogenic clones, but is essential for thymic formation of islet-specific Foxp3-expressing CD4 T cells. The absence of IL-2 results in the expansion of low-avidity Foxp3(-) islet-reactive CD4 T cells. The mechanism by which IL-2 prevents diabetes is therefore through the establishment of a repertoire of islet-reactive Foxp3(+) T cells within the thymus, and limitation of the peripheral activation of low-avidity islet-reactive T cells that normally escape thymic negative selection.

+view abstract Immunology and cell biology, PMID: 17372610 2007

A Saudemont, K Okkenhaug, F Colucci Immunology

NK cell (natural killer cells) are lymphocytes of innate immunity that kill tumour cells and respond to infections, without prior stimulation. A balance of activating and inhibitory signals regulates NK cell cytotoxicity, but the molecular mechanisms are not fully understood. General inhibitors of PI3K (phosphoinositide 3-kinase) suppress cytotoxicity in human and mouse NK cells. However, which isoforms and how they regulate NK cell activation is unknown, and no data have been published on mice carrying PI3K mutations. p110delta expression is restricted to leucocytes, where it plays central roles in lymphocyte development and signalling. We have used mice carrying a catalytically inactive mutant form of p110delta in order to determine its role in NK cell biology. We show here that p110delta is not required to kill tumour cells, but unexpectedly p110delta mutant mice failed to fully reject transplanted lymphomas. Our results show for the first time a critical role for p110delta in NK cell biology in vivo.

+view abstract Biochemical Society transactions, PMID: 17371233 2007

DT Patton, F Garçon, K Okkenhaug Immunology

PI3Ks (phosphoinositide 3-kinases) regulate diverse cellular functions such as metabolism, growth, gene expression and migration. The p110delta isoform of PI3K is mainly expressed in cells of the immune system and contributes to cellular and humoral immunity. In the thymus, p110delta and p110gamma play complementary roles in regulating the transition through key developmental checkpoints. In addition, p110delta regulates the differentiation of peripheral Th (helper T-cells) towards the Th1 and Th2 lineages. Moreover, p110delta is critical for Treg (regulatory T-cell) function. Here, we review the role of PI3Ks in T-cell development and function.

+view abstract Biochemical Society transactions, PMID: 17371229 2007

M Spivakov, AG Fisher

Pluripotent stem cells, similar to more restricted stem cells, are able to both self-renew and generate differentiated progeny. Although this dual functionality has been much studied, the search for molecular signatures of 'stemness' and pluripotency is only now beginning to gather momentum. While the focus of much of this work has been on the transcriptional features of embryonic stem cells, recent studies have indicated the importance of unique epigenetic profiles that keep key developmental genes 'poised' in a repressed but activatable state. Determining how these epigenetic features relate to the transcriptional signatures of ES cells, and whether they are also important in other types of stem cell, is a key challenge for the future.

+view abstract Nature Reviews Genetics, PMID: 17363975 2007

JM Williams, TR Pettitt, W Powell, J Grove, CO Savage, MJ Wakelam Signalling

Patients with certain forms of systematic vasculitis, such as Wegener's granulomatosis, have circulating antineutrophil cytoplasmic antibodies (ANCA). These inappropriately stimulate circulating neutrophils adhere to and thereby obstruct small vessels. This, together with ANCA-induced degranulation and an oxidative burst, leads to local tissue damage. The signaling pathways that are activated by ANCA IgG are distinct from those that are involved in normal neutrophil activation. This study shows that diacylglycerol kinase is selectively activated by ANCA and that the generated phosphatidic acid is responsible for promoting neutrophil adhesion, in part through integrin activation. The data presented point to diacylglycerol kinase alpha as a novel but selective target for the development of drugs to treat this potentially fatal disorder.

+view abstract Journal of the American Society of Nephrology : JASN, PMID: 17360949 2007

Liston A, Farr AG, Chen Z, Benoist C, Mathis D, Manley NR, Rudensky AY Immunology

Foxp3 is essential for the commitment of differentiating thymocytes to the regulatory CD4(+) T (T reg) cell lineage. In humans and mice with a genetic Foxp3 deficiency, absence of this critical T reg cell population was suggested to be responsible for the severe autoimmune lesions. Recently, it has been proposed that in addition to T reg cells, Foxp3 is also expressed in thymic epithelial cells where it is involved in regulation of early thymocyte differentiation and is required to prevent autoimmunity. Here, we used genetic tools to demonstrate that the thymic epithelium does not express Foxp3. Furthermore, we formally showed that genetic abatement of Foxp3 in the hematopoietic compartment, i.e. in T cells, is both necessary and sufficient to induce the autoimmune lesions associated with Foxp3 loss. In contrast, deletion of a conditional Foxp3 allele in thymic epithelial cells did not result in detectable changes in thymocyte differentiation or pathology. Therefore, in mice the only known role for Foxp3 remains promotion of T reg cell differentiation within the T cell lineage, whereas there is no role for Foxp3 in thymic epithelial cells.

+view abstract The Journal of experimental medicine, PMID: 17353370 2007

D Corcos

The B cell receptor (BCR) is required for stimulation of B cells by antigen, and is also involved in the negative selection of autoreactive B cells. In the past few years, a constitutive ligand-independent signaling activity of the BCR has been demonstrated. In this paper, the various findings are summarized and their interpretation and their significance, both in pathology and in physiology discussed. The constitutive activity of the BCR may be important for tumor formation, at least in the case of heavy-chain diseases, neoplastic proliferations developed from B cells. A large body of evidence suggests that this activity could be required for B cell survival and would play a role in B cell development as a process monitoring BCR functionality. A model explaining signaling in the absence of antigen as a function of dimer formation is proposed. The putative constitutive activity of the pre-BCR is also discussed.

+view abstract Archivum immunologiae et therapiae experimentalis, PMID: 17347803 0

Ross SH, Lindsay Y, Safrany ST, Lorenzo O, Villa F, Toth R, Clague MJ, Downes CP, Leslie NR

The Protein Tyrosine Phosphatase (PTP) family comprises a large and diverse group of enzymes, regulating a range of biological processes through de-phosphorylation of many proteins and lipids. These enzymes share a catalytic mechanism that requires a reduced and reactive cysteine nucleophile, making them potentially sensitive to inactivation and regulation by oxidation. Analysis of ten PTPs identified substantial differences in the sensitivity of these enzymes to oxidation in vitro. More detailed experiments confirmed the following rank order of sensitivity: PTEN and Sac1>PTPL1/FAP-1>myotubularins. When the apparent sensitivity to oxidation of these PTPs in cells treated with hydrogen peroxide was analysed, this correlated well with the observed sensitivities to oxidation in vitro. These data suggested that different PTPs may fall into at least three different classes with respect to mechanisms of cellular redox regulation. 1. PTEN and Sac1 were readily and reversibly oxidised in vitro and in cells treated with hydrogen peroxide 2. PTPL1 appeared to be resistant to oxidation in cells, correlating with its sensitivity to reduction by glutathione in vitro 3. The myotubularin family of lipid phosphatases was almost completely resistant to oxidation in vitro and in cells. Our results show that sensitivity to reversible oxidation is not a necessary characteristic of the PTPs and imply that such sensitivity has evolved as a regulatory mechanism for some of this large family, but not others.

+view abstract Cellular signalling, PMID: 17346927 2007

Powner DJ, Pettitt TR, Anderson R, Nash GB, Wakelam MJ Signalling

The pathways regulating integrin-mediated adhesion during neutrophil migration are incompletely defined. Using a flow-based model in which human neutrophils rolling on P-selectin were activated to migrate by the chemoattractant peptide fMLP, we investigated the role of phospholipase D (PLD). fMLP-stimulated PLD generation of phosphatidate (PtdOH); while inhibition of PtdOH production with butan-1-ol had no effect on the initial immobilisation of rolling neutrophils (supported by activation of constitutively surface-expressed beta(2)-integrin CD11b/CD18) it impaired longer-term stability of adhesion and reduced the rate of migration (supported by activation of de novo-exocytosed CD11b/CD18). PtdOH regulated these processes by controlling activation of exocytosed CD11b/CD18, and appeared to act by directly stimulating phosphatidylinositol 4-phosphate 5-kinase type I to generate phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P(2)). Cell-permeable PtdIns(4,5)P(2) recovered migration of neutrophils after PLD inhibition; PtdIns(4,5)P(2) appeared to act by promoting talin binding to CD18 and hence activating CD11b/CD18, as migration was inhibited when neutrophils were loaded with peptides previously shown to block the interaction between PtdIns(4,5)P(2) and talin or talin and CD18. Thus, these data indicate that PLD-synthesised PtdOH stimulates the generation of PtdIns(4,5)P(2), which in turn mediates talin binding to, and activation of, CD11b/CD18 required for neutrophil stable adhesion and migration.

+view abstract Molecular immunology, PMID: 17346796 2007

SJ Cook, SJ Morley Signalling

The control of cell growth, that is cell size, is largely controlled by mTOR (the mammalian target of rapamycin), a large serine/threonine protein kinase that regulates ribosome biogenesis and protein translation. mTOR activity is regulated both by the availability of growth factors, such as insulin/IGF-1 (insulin-like growth factor 1), and by nutrients, notably the supply of certain key amino acids. The last few years have seen a remarkable increase in our understanding of the canonical, growth factor-regulated pathway for mTOR activation, which is mediated by the class I PI3Ks (phosphoinositide 3-kinases), PKB (protein kinase B), TSC1/2 (the tuberous sclerosis complex) and the small GTPase, Rheb. However, the nutrient-responsive input into mTOR is important in its own right and is also required for maximal activation of mTOR signalling by growth factors. Despite this, the details of the nutrient-responsive signalling pathway(s) controlling mTOR have remained elusive, although recent studies have suggested a role for the class III PI3K hVps34. In this issue of the Biochemical Journal, Findlay et al. demonstrate that the protein kinase MAP4K3 [mitogen-activated protein kinase kinase kinase kinase-3, a Ste20 family protein kinase also known as GLK (germinal centre-like kinase)] is a new component of the nutrient-responsive pathway. MAP4K3 activity is stimulated by administration of amino acids, but not growth factors, and this is insensitive to rapamycin, most likely placing MAP4K3 upstream of mTOR. Indeed, MAP4K3 is required for phosphorylation of known mTOR targets such as S6K1 (S6 kinase 1), and overexpression of MAP4K3 promotes the rapamycin-sensitive phosphorylation of these same targets. Finally, knockdown of MAP4K3 levels causes a decrease in cell size. The results suggest that MAP4K3 is a new component in the nutrient-responsive pathway for mTOR activation and reveal a completely new function for MAP4K3 in promoting cell growth. Given that mTOR activity is frequently deregulated in cancer, there is much interest in new strategies for inhibition of this pathway. In this context, MAP4K3 looks like an attractive drug target since inhibitors of this enzyme should switch off mTOR, thereby inhibiting cell growth and proliferation, and promoting apoptosis.

+view abstract The Biochemical journal, PMID: 17346240 2007

R Adalbert, J Gilley, MP Coleman Signalling

Mutations in amyloid precursor protein (APP), tau and apolipoprotein E4 (ApoE4) lead to Alzheimer's disease (AD) or related pathologies. Pathogenesis and interactions between these pathways have been studied in mouse models. Here, we highlight the fact that axons are important sites of cellular pathology in each pathway and propose that pathway convergence at the molecular level might occur in axons. Recent developments suggest that axonal transport of APP influences beta-amyloid deposition and that tau regulates axonal transport. ApoE4 influences both axonal tau phosphorylation and amyloid-induced neurite pathology. Thus, a better understanding of axonal events in AD might help connect the pathogenic mechanisms of beta-amyloid, ApoE4 and tau, indicating the most important steps for therapeutic targeting.

+view abstract Trends in molecular medicine, PMID: 17344096 2007

Downes CP, Ross S, Maccario H, Perera N, Davidson L, Leslie NR

+view abstract Advances in enzyme regulation, PMID: 17343901 2007