G2Cdb::Gene report

Gene id
Gene symbol
Homo sapiens
exocyst complex component 4
G00000295 (Mus musculus)

Databases (8)

Curated Gene
OTTHUMG00000023872 (Vega human gene)
ENSG00000131558 (Ensembl human gene)
60412 (Entrez Gene)
631 (G2Cdb plasticity & disease)
EXOC4 (GeneCards)
608185 (OMIM)
Marker Symbol
HGNC:30389 (HGNC)
Protein Sequence
Q96A65 (UniProt)

Synonyms (5)

  • KIAA1699
  • MGC27170
  • REC8
  • SEC8
  • Sec8p

Literature (31)

Pubmed - other

  • Screening for replication of genome-wide SNP associations in sporadic ALS.

    Cronin S, Tomik B, Bradley DG, Slowik A and Hardiman O

    Department of Clinical Neurological Sciences, Royal College of Surgeons in Ireland, Dublin 2, Ireland. scronin@rcsi.ie

    We recently reported a joint analysis of genome-wide association (GWA) data on 958 sporadic amyotrophic lateral sclerosis (ALS) cases and 932 controls from Ireland and the publicly available data sets from the United States and the Netherlands. The strongest pooled association was rs10260404 in the dipeptidyl-peptidase 6 (DPP6) gene. Here, we sought confirmation of joint analysis signals in both an expanded Irish and a Polish ALS cohort. Among 287 522 autosomal single-nucleotide polymorphisms (SNPs), 27 were commonly associated on joint analysis of the Irish, US and Dutch GWAs. These 27 SNPs were genotyped in an expanded Irish cohort (312 patients with SALS; 259 controls) and an additional Polish cohort (218 patients; 356 controls). Eleven SNPs, including rs10260404, reached a final P-value below 0.05 in the Irish cohort. In the Polish cohort, only one SNP, rs6299711, showed nominal association with ALS. Pooling of data for 1267 patients with ALS and 1336 control subjects did not identify any association reaching Bonferroni significance (P<1.74 x 10(-7)). The present strategy did not reveal any consistently associated SNP across four populations. The result for DPP6 is surprising, as it has been replicated elsewhere. We discuss the possible interpretations and implications of these findings for future ALS GWA studies both within and between populations.

    European journal of human genetics : EJHG 2009;17;2;213-8

  • The interaction of IQGAP1 with the exocyst complex is required for tumor cell invasion downstream of Cdc42 and RhoA.

    Sakurai-Yageta M, Recchi C, Le Dez G, Sibarita JB, Daviet L, Camonis J, D'Souza-Schorey C and Chavrier P

    Institut Curie, Centre de Recherche, Paris F-75248, France.

    Invadopodia are actin-based membrane protrusions formed at contact sites between invasive tumor cells and the extracellular matrix with matrix proteolytic activity. Actin regulatory proteins participate in invadopodia formation, whereas matrix degradation requires metalloproteinases (MMPs) targeted to invadopodia. In this study, we show that the vesicle-tethering exocyst complex is required for matrix proteolysis and invasion of breast carcinoma cells. We demonstrate that the exocyst subunits Sec3 and Sec8 interact with the polarity protein IQGAP1 and that this interaction is triggered by active Cdc42 and RhoA, which are essential for matrix degradation. Interaction between IQGAP1 and the exocyst is necessary for invadopodia activity because enhancement of matrix degradation induced by the expression of IQGAP1 is lost upon deletion of the exocyst-binding site. We further show that the exocyst and IQGAP1 are required for the accumulation of cell surface membrane type 1 MMP at invadopodia. Based on these results, we propose that invadopodia function in tumor cells relies on the coordination of cytoskeletal assembly and exocytosis downstream of Rho guanosine triphosphatases.

    The Journal of cell biology 2008;181;6;985-98

  • Polymorphisms near EXOC4 and LRGUK on chromosome 7q32 are associated with Type 2 Diabetes and fasting glucose; the NHLBI Family Heart Study.

    Laramie JM, Wilk JB, Williamson SL, Nagle MW, Latourelle JC, Tobin JE, Province MA, Borecki IB and Myers RH

    Department of Neurology, Boston University School of Medicine, Boston, MA, USA. laramiej@gmail.com

    Background: The chromosome 7q32 region is linked to metabolic syndrome and obesity related traits in the Family Heart Study. As part of a fine mapping study of the region, we evaluated the relationship of polymorphisms to fasting glucose levels and Type 2 diabetes.

    Methods: Thirty-nine HapMap defined tag SNPs in a 1.08 Mb region and a novel deletion polymorphism were genotyped in 2,603 participants of the NHLBI Family Heart Study (FHS). Regression modeling, adjusting for BMI, age, sex, smoking and the TCF7L2 polymorphism, was used to evaluate the association of these polymorphisms with T2D and fasting glucoses levels.

    Results: The deletion polymorphism confers a protective effect for T2D, with homozygous deletion carriers having a 53% reduced risk compared to non-deleted carriers. Among non-diabetics, the deletion was significantly associated with lower fasting glucose levels in men (p = 0.038) but not women (p = 0.118). In addition, seven SNPs near the deletion were significantly associated (p < 0.01) to diabetes.

    Conclusion: Chromosome 7q32 contains both SNPs and a deletion that were associated to T2D. Although the deletion region contains several islands of strongly conserved sequence, it is not known to contain a transcribed gene. The closest nearby gene, EXOC4, is involved in insulin-stimulated glucose transport and may be a candidate for this association. Further work is needed to determine if the deletion represents a functional variant or may be in linkage disequilibrium with a functional mutation influencing EXOC4 or another nearby gene.

    Funded by: NCRR NIH HHS: 1S10RR163736-01A1; NHLBI NIH HHS: R01 HL68891-05; PHS HHS: R01 D068336-03

    BMC medical genetics 2008;9;46

  • Involvement of Exoc3l, a protein structurally related to the exocyst subunit Sec6, in insulin secretion.

    Saito T, Shibasaki T and Seino S

    Division of Cellular and Molecular Medicine, Kobe University Graduate School of Medicine, Kobe, Japan.

    The exocyst is an octameric complex involved in docking or tethering of secretory vesicles to fusion sites of the plasma membrane. Sec6 is the core subunit of the exocyst complex. Here we identify an isoform of Sec6, deposited as Exocyst complex component 3-like (Exoc3l) in the database, by in silico screening using rat Sec6 as a probe. The amino acid sequence of Exoc3l has 31% identity and 53% similarity with that of Sec6. RT-PCR analysis reveals that Exoc3l is expressed in insulin-secreting MIN6 cells as well as in various tissues including pancreatic islets and brain. In co-immunoprecipitation experiments, Exoc3l was found to interact with Sec5, Sec8, and Sec10, all of which are binding partners of Sec6 in the exocyst complex. Furthermore, overexpression of a deletion mutant of Exoc3l in MIN6 cells suppressed glucose-stimulated secretion. These results suggest that Exoc3l is involved in regulated exocytosis of insulin granules.

    Biomedical research (Tokyo, Japan) 2008;29;2;85-91

  • Final stages of cytokinesis and midbody ring formation are controlled by BRUCE.

    Pohl C and Jentsch S

    Department of Molecular Cell Biology, Max Planck Institute of Biochemistry, Am Klopferspitz 18, 82152 Martinsried, Germany.

    Cytokinesis involves the formation of a cleavage furrow, followed by abscission, the cutting of the midbody channel, the final bridge between dividing cells. Recently, the midbody ring became known as central for abscission, but its regulation remains enigmatic. Here, we identify BRUCE, a 528 kDa multifunctional protein, which processes ubiquitin-conjugating activity, as a major regulator of abscission. During cytokinesis, BRUCE moves from the vesicular system to the midbody ring and serves as a platform for the membrane delivery machinery and mitotic regulators. Depletion of BRUCE in cell cultures causes defective abscission and cytokinesis-associated apoptosis, accompanied by a block of vesicular targeting and defective formation of the midbody and the midbody ring. Notably, ubiquitin relocalizes from midbody microtubules to the midbody ring during cytokinesis, and depletion of BRUCE disrupts this process. We propose that BRUCE coordinates multiple steps required for abscission and that ubiquitylation may be a crucial trigger.

    Cell 2008;132;5;832-45

  • Framingham Heart Study 100K Project: genome-wide associations for blood pressure and arterial stiffness.

    Levy D, Larson MG, Benjamin EJ, Newton-Cheh C, Wang TJ, Hwang SJ, Vasan RS and Mitchell GF

    The National Heart, Lung, and Blood Institute's Framingham Heart Study, Framingham, MA, USA. Levyd@nih.gov

    Background: About one quarter of adults are hypertensive and high blood pressure carries increased risk for heart disease, stroke, kidney disease and death. Increased arterial stiffness is a key factor in the pathogenesis of systolic hypertension and cardiovascular disease. Substantial heritability of blood-pressure (BP) and arterial-stiffness suggests important genetic contributions.

    Methods: In Framingham Heart Study families, we analyzed genome-wide SNP (Affymetrix 100K GeneChip) associations with systolic (SBP) and diastolic (DBP) BP at a single examination in 1971-1975 (n = 1260), at a recent examination in 1998-2001 (n = 1233), and long-term averaged SBP and DBP from 1971-2001 (n = 1327, mean age 52 years, 54% women) and with arterial stiffness measured by arterial tonometry (carotid-femoral and carotid-brachial pulse wave velocity, forward and reflected pressure wave amplitude, and mean arterial pressure; 1998-2001, n = 644). In primary analyses we used generalized estimating equations in models for an additive genetic effect to test associations between SNPs and phenotypes of interest using multivariable-adjusted residuals. A total of 70,987 autosomal SNPs with minor allele frequency > or = 0.10, genotype call rate > or = 0.80, and Hardy-Weinberg equilibrium p > or = 0.001 were analyzed. We also tested for association of 69 SNPs in six renin-angiotensin-aldosterone pathway genes with BP and arterial stiffness phenotypes as part of a candidate gene search.

    Results: In the primary analyses, none of the associations attained genome-wide significance. For the six BP phenotypes, seven SNPs yielded p values < 10(-5). The lowest p-values for SBP and DBP respectively were rs10493340 (p = 1.7 x 10(-6)) and rs1963982 (p = 3.3 x 10(-6)). For the five tonometry phenotypes, five SNPs had p values < 10(-5); lowest p-values were for reflected wave (rs6063312, p = 2.1 x 10(-6)) and carotid-brachial pulse wave velocity (rs770189, p = 2.5 x 10(-6)) in MEF2C, a regulator of cardiac morphogenesis. We found only weak association of SNPs in the renin-angiotensin-aldosterone pathway with BP or arterial stiffness.

    Conclusion: These results of genome-wide association testing for blood pressure and arterial stiffness phenotypes in an unselected community-based sample of adults may aid in the identification of the genetic basis of hypertension and arterial disease, help identify high risk individuals, and guide novel therapies for hypertension. Additional studies are needed to replicate any associations identified in these analyses.

    Funded by: NCRR NIH HHS: 1S10RR163736-01A1; NHLBI NIH HHS: K24 HL004334, K24-HL04334, N01-HC 25195, N01HC25195, R01 HL060040, R01 HL070100, R01-HL60040, R01-HL70100

    BMC medical genetics 2007;8 Suppl 1;S3

  • Systematic analysis of the protein interaction network for the human transcription machinery reveals the identity of the 7SK capping enzyme.

    Jeronimo C, Forget D, Bouchard A, Li Q, Chua G, Poitras C, Thérien C, Bergeron D, Bourassa S, Greenblatt J, Chabot B, Poirier GG, Hughes TR, Blanchette M, Price DH and Coulombe B

    Laboratory of Gene Transcription and Proteomics Discovery Platform, Institut de Recherches Cliniques de Montréal, Montréal, QC, Canada.

    We have performed a survey of soluble human protein complexes containing components of the transcription and RNA processing machineries using protein affinity purification coupled to mass spectrometry. Thirty-two tagged polypeptides yielded a network of 805 high-confidence interactions. Remarkably, the network is significantly enriched in proteins that regulate the formation of protein complexes, including a number of previously uncharacterized proteins for which we have inferred functions. The RNA polymerase II (RNAP II)-associated proteins (RPAPs) are physically and functionally associated with RNAP II, forming an interface between the enzyme and chaperone/scaffolding proteins. BCDIN3 is the 7SK snRNA methylphosphate capping enzyme (MePCE) present in an snRNP complex containing both RNA processing and transcription factors, including the elongation factor P-TEFb. Our results define a high-density protein interaction network for the mammalian transcription machinery and uncover multiple regulatory factors that target the transcription machinery.

    Funded by: Canadian Institutes of Health Research: 14309-3, 82851-1

    Molecular cell 2007;27;2;262-74

  • Large-scale mapping of human protein-protein interactions by mass spectrometry.

    Ewing RM, Chu P, Elisma F, Li H, Taylor P, Climie S, McBroom-Cerajewski L, Robinson MD, O'Connor L, Li M, Taylor R, Dharsee M, Ho Y, Heilbut A, Moore L, Zhang S, Ornatsky O, Bukhman YV, Ethier M, Sheng Y, Vasilescu J, Abu-Farha M, Lambert JP, Duewel HS, Stewart II, Kuehl B, Hogue K, Colwill K, Gladwish K, Muskat B, Kinach R, Adams SL, Moran MF, Morin GB, Topaloglou T and Figeys D

    Protana, Toronto, Ontario, Canada.

    Mapping protein-protein interactions is an invaluable tool for understanding protein function. Here, we report the first large-scale study of protein-protein interactions in human cells using a mass spectrometry-based approach. The study maps protein interactions for 338 bait proteins that were selected based on known or suspected disease and functional associations. Large-scale immunoprecipitation of Flag-tagged versions of these proteins followed by LC-ESI-MS/MS analysis resulted in the identification of 24,540 potential protein interactions. False positives and redundant hits were filtered out using empirical criteria and a calculated interaction confidence score, producing a data set of 6463 interactions between 2235 distinct proteins. This data set was further cross-validated using previously published and predicted human protein interactions. In-depth mining of the data set shows that it represents a valuable source of novel protein-protein interactions with relevance to human diseases. In addition, via our preliminary analysis, we report many novel protein interactions and pathway associations.

    Molecular systems biology 2007;3;89

  • A probability-based approach for high-throughput protein phosphorylation analysis and site localization.

    Beausoleil SA, Villén J, Gerber SA, Rush J and Gygi SP

    Department of Cell Biology, Harvard Medical School, 240 Longwood Ave., Boston, Massachusetts 02115, USA.

    Data analysis and interpretation remain major logistical challenges when attempting to identify large numbers of protein phosphorylation sites by nanoscale reverse-phase liquid chromatography/tandem mass spectrometry (LC-MS/MS) (Supplementary Figure 1 online). In this report we address challenges that are often only addressable by laborious manual validation, including data set error, data set sensitivity and phosphorylation site localization. We provide a large-scale phosphorylation data set with a measured error rate as determined by the target-decoy approach, we demonstrate an approach to maximize data set sensitivity by efficiently distracting incorrect peptide spectral matches (PSMs), and we present a probability-based score, the Ascore, that measures the probability of correct phosphorylation site localization based on the presence and intensity of site-determining ions in MS/MS spectra. We applied our methods in a fully automated fashion to nocodazole-arrested HeLa cell lysate where we identified 1,761 nonredundant phosphorylation sites from 491 proteins with a peptide false-positive rate of 1.3%.

    Funded by: NHGRI NIH HHS: HG03456; NIGMS NIH HHS: GM67945

    Nature biotechnology 2006;24;10;1285-92

  • The LIFEdb database in 2006.

    Mehrle A, Rosenfelder H, Schupp I, del Val C, Arlt D, Hahne F, Bechtel S, Simpson J, Hofmann O, Hide W, Glatting KH, Huber W, Pepperkok R, Poustka A and Wiemann S

    Division Molecular Genome Analysis, German Cancer Research Center, Im Neuenheimer Feld 580, D-69120 Heidelberg, Germany. a.mehrle@dkfz.de

    LIFEdb (http://www.LIFEdb.de) integrates data from large-scale functional genomics assays and manual cDNA annotation with bioinformatics gene expression and protein analysis. New features of LIFEdb include (i) an updated user interface with enhanced query capabilities, (ii) a configurable output table and the option to download search results in XML, (iii) the integration of data from cell-based screening assays addressing the influence of protein-overexpression on cell proliferation and (iv) the display of the relative expression ('Electronic Northern') of the genes under investigation using curated gene expression ontology information. LIFEdb enables researchers to systematically select and characterize genes and proteins of interest, and presents data and information via its user-friendly web-based interface.

    Nucleic acids research 2006;34;Database issue;D415-8

  • Association between single-nucleotide polymorphisms in the SEC8L1 gene, which encodes a subunit of the exocyst complex, and rheumatoid arthritis in a Japanese population.

    Hamada D, Takata Y, Osabe D, Nomura K, Shinohara S, Egawa H, Nakano S, Shinomiya F, Scafe CR, Reeve VM, Miyamoto T, Moritani M, Kunika K, Inoue H, Yasui N and Itakura M

    Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan.

    Objective: To identify rheumatoid arthritis (RA) susceptibility genes in a Japanese population by conducting a large-scale case-control association analysis and linkage disequilibrium (LD) mapping on chromosome 7q31-34, a candidate susceptibility locus identified in a preliminary genome-wide scan in 53 Japanese families, using single-nucleotide polymorphisms (SNPs).

    Methods: We prepared 728 dense, evenly spaced SNPs with a minor allele frequency >0.15 in each gene locus on chromosome 7q31-34. Using these SNPs, a 2-stage case-control analysis was performed on 760 RA patients (157 men and 603 women) and 806 non-RA controls (189 men and 617 women). Haplotypes and LD mapping results were assessed based on SNP genotypes in 380 controls.

    Results: Forty-eight SNPs showed allele associations (P < 0.05) in the first set of DNA samples (380 RA cases and 380 non-RA controls; first-stage analysis). For 4 of the SNPs in the SEC8L1 gene, the association was replicated (P < 0.05) in the second, independent set of DNA samples (an additional 380 RA cases and 380 non-RA controls; second-stage analysis). When data from the 2 groups were combined, the most significant allele association was observed with SNP 441, an intronic SNP of the SEC8L1 gene (P = 0.000059). The SEC8L1 SNPs with significant allele associations were all located in a single conserved LD block (block 4). Haplotype analysis revealed the disease-risk (P = 0.0015) and disease-protective (P = 0.0000062) haplotypes. Resequencing of coding exons within block 4 did not identify any nonsynonymous SNPs. Real-time quantitative polymerase chain reaction revealed that SEC8L1 was expressed ubiquitously in human tissues, including fibroblast-like synoviocytes from RA patients.

    Conclusion: Our locus-wide association and LD analyses identified intronic SNPs and haplotypes in the SEC8L1 gene that are strongly associated with RA. We propose that SEC8L1, which encodes a component of the exocyst complex, is a candidate susceptibility gene for RA in the Japanese population.

    Arthritis and rheumatism 2005;52;5;1371-80

  • From ORFeome to biology: a functional genomics pipeline.

    Wiemann S, Arlt D, Huber W, Wellenreuther R, Schleeger S, Mehrle A, Bechtel S, Sauermann M, Korf U, Pepperkok R, Sültmann H and Poustka A

    Molecular Genome Analysis, German Cancer Research Center, 69120 Heidelberg, Germany. s.wiemann@dkfz.de

    As several model genomes have been sequenced, the elucidation of protein function is the next challenge toward the understanding of biological processes in health and disease. We have generated a human ORFeome resource and established a functional genomics and proteomics analysis pipeline to address the major topics in the post-genome-sequencing era: the identification of human genes and splice forms, and the determination of protein localization, activity, and interaction. Combined with the understanding of when and where gene products are expressed in normal and diseased conditions, we create information that is essential for understanding the interplay of genes and proteins in the complex biological network. We have implemented bioinformatics tools and databases that are suitable to store, analyze, and integrate the different types of data from high-throughput experiments and to include further annotation that is based on external information. All information is presented in a Web database (http://www.dkfz.de/LIFEdb). It is exploited for the identification of disease-relevant genes and proteins for diagnosis and therapy.

    Genome research 2004;14;10B;2136-44

  • A physical and functional map of the human TNF-alpha/NF-kappa B signal transduction pathway.

    Bouwmeester T, Bauch A, Ruffner H, Angrand PO, Bergamini G, Croughton K, Cruciat C, Eberhard D, Gagneur J, Ghidelli S, Hopf C, Huhse B, Mangano R, Michon AM, Schirle M, Schlegl J, Schwab M, Stein MA, Bauer A, Casari G, Drewes G, Gavin AC, Jackson DB, Joberty G, Neubauer G, Rick J, Kuster B and Superti-Furga G

    Cellzome AG, Meyerhofstrasse 1, 69117 Heidelberg, Germany. tewis.bouwmeester@cellzome.com

    Signal transduction pathways are modular composites of functionally interdependent sets of proteins that act in a coordinated fashion to transform environmental information into a phenotypic response. The pro-inflammatory cytokine tumour necrosis factor (TNF)-alpha triggers a signalling cascade, converging on the activation of the transcription factor NF-kappa B, which forms the basis for numerous physiological and pathological processes. Here we report the mapping of a protein interaction network around 32 known and candidate TNF-alpha/NF-kappa B pathway components by using an integrated approach comprising tandem affinity purification, liquid-chromatography tandem mass spectrometry, network analysis and directed functional perturbation studies using RNA interference. We identified 221 molecular associations and 80 previously unknown interactors, including 10 new functional modulators of the pathway. This systems approach provides significant insight into the logic of the TNF-alpha/NF-kappa B pathway and is generally applicable to other pathways relevant to human disease.

    Nature cell biology 2004;6;2;97-105

  • Complete sequencing and characterization of 21,243 full-length human cDNAs.

    Ota T, Suzuki Y, Nishikawa T, Otsuki T, Sugiyama T, Irie R, Wakamatsu A, Hayashi K, Sato H, Nagai K, Kimura K, Makita H, Sekine M, Obayashi M, Nishi T, Shibahara T, Tanaka T, Ishii S, Yamamoto J, Saito K, Kawai Y, Isono Y, Nakamura Y, Nagahari K, Murakami K, Yasuda T, Iwayanagi T, Wagatsuma M, Shiratori A, Sudo H, Hosoiri T, Kaku Y, Kodaira H, Kondo H, Sugawara M, Takahashi M, Kanda K, Yokoi T, Furuya T, Kikkawa E, Omura Y, Abe K, Kamihara K, Katsuta N, Sato K, Tanikawa M, Yamazaki M, Ninomiya K, Ishibashi T, Yamashita H, Murakawa K, Fujimori K, Tanai H, Kimata M, Watanabe M, Hiraoka S, Chiba Y, Ishida S, Ono Y, Takiguchi S, Watanabe S, Yosida M, Hotuta T, Kusano J, Kanehori K, Takahashi-Fujii A, Hara H, Tanase TO, Nomura Y, Togiya S, Komai F, Hara R, Takeuchi K, Arita M, Imose N, Musashino K, Yuuki H, Oshima A, Sasaki N, Aotsuka S, Yoshikawa Y, Matsunawa H, Ichihara T, Shiohata N, Sano S, Moriya S, Momiyama H, Satoh N, Takami S, Terashima Y, Suzuki O, Nakagawa S, Senoh A, Mizoguchi H, Goto Y, Shimizu F, Wakebe H, Hishigaki H, Watanabe T, Sugiyama A, Takemoto M, Kawakami B, Yamazaki M, Watanabe K, Kumagai A, Itakura S, Fukuzumi Y, Fujimori Y, Komiyama M, Tashiro H, Tanigami A, Fujiwara T, Ono T, Yamada K, Fujii Y, Ozaki K, Hirao M, Ohmori Y, Kawabata A, Hikiji T, Kobatake N, Inagaki H, Ikema Y, Okamoto S, Okitani R, Kawakami T, Noguchi S, Itoh T, Shigeta K, Senba T, Matsumura K, Nakajima Y, Mizuno T, Morinaga M, Sasaki M, Togashi T, Oyama M, Hata H, Watanabe M, Komatsu T, Mizushima-Sugano J, Satoh T, Shirai Y, Takahashi Y, Nakagawa K, Okumura K, Nagase T, Nomura N, Kikuchi H, Masuho Y, Yamashita R, Nakai K, Yada T, Nakamura Y, Ohara O, Isogai T and Sugano S

    Helix Research Institute, 1532-3 Yana, Kisarazu, Chiba 292-0812, Japan.

    As a base for human transcriptome and functional genomics, we created the "full-length long Japan" (FLJ) collection of sequenced human cDNAs. We determined the entire sequence of 21,243 selected clones and found that 14,490 cDNAs (10,897 clusters) were unique to the FLJ collection. About half of them (5,416) seemed to be protein-coding. Of those, 1,999 clusters had not been predicted by computational methods. The distribution of GC content of nonpredicted cDNAs had a peak at approximately 58% compared with a peak at approximately 42%for predicted cDNAs. Thus, there seems to be a slight bias against GC-rich transcripts in current gene prediction procedures. The rest of the cDNAs unique to the FLJ collection (5,481) contained no obvious open reading frames (ORFs) and thus are candidate noncoding RNAs. About one-fourth of them (1,378) showed a clear pattern of splicing. The distribution of GC content of noncoding cDNAs was narrow and had a peak at approximately 42%, relatively low compared with that of protein-coding cDNAs.

    Nature genetics 2004;36;1;40-5

  • The exocyst complex in polarized exocytosis.

    Hsu SC, TerBush D, Abraham M and Guo W

    Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, New Jersey 08854, USA.

    Exocytosis is an essential membrane traffic event mediating the secretion of intracellular protein contents such as hormones and neurotransmitters as well as the incorporation of membrane proteins and lipids to specific domains of the plasma membrane. As a fundamental cell biological process, exocytosis is crucial for cell growth, cell-cell communication, and cell polarity establishment. For most eukaryotic cells exocytosis is polarized. A multiprotein complex, named the exocyst, is required for polarized exocytosis from yeast to mammals. The exocyst consists of eight components: Sec3, Sec5, Sec6, Sec8, Sec10, Sec15, Exo70, and Exo84. They are localized to sites of active exocytosis, where they mediate the targeting and tethering of post-Golgi secretory vesicles for subsequent membrane fusion. Here we review the progress made in the understanding of the exocyst and its role in polarized exocytosis.

    International review of cytology 2004;233;243-65

  • Ral GTPases regulate exocyst assembly through dual subunit interactions.

    Moskalenko S, Tong C, Rosse C, Mirey G, Formstecher E, Daviet L, Camonis J and White MA

    Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75235-9039, USA.

    Ral GTPases have been implicated in the regulation of a variety of dynamic cellular processes including proliferation, oncogenic transformation, actin-cytoskeletal dynamics, endocytosis, and exocytosis. Recently the Sec6/8 complex, or exocyst, a multisubunit complex facilitating post-Golgi targeting of distinct subclasses of secretory vesicles, has been identified as a bona fide Ral effector complex. Ral GTPases regulate exocyst-dependent vesicle trafficking and are required for exocyst complex assembly. Sec5, a membrane-associated exocyst subunit, has been identified as a direct target of activated Ral; however, the mechanism by which Ral can modulate exocyst assembly is unknown. Here we report that an additional component of the exocyst, Exo84, is a direct target of activated Ral. We provide evidence that mammalian exocyst components are present as distinct subcomplexes on vesicles and the plasma membrane and that Ral GTPases regulate the assembly interface of a full octameric exocyst complex through interaction with Sec5 and Exo84.

    Funded by: NCI NIH HHS: CA71443

    The Journal of biological chemistry 2003;278;51;51743-8

  • Exocyst complex subunit sec8 binds to postsynaptic density protein-95 (PSD-95): a novel interaction regulated by cypin (cytosolic PSD-95 interactor).

    Riefler GM, Balasingam G, Lucas KG, Wang S, Hsu SC and Firestein BL

    Department of Cell Biology and Neuroscience, Rutgers, The State University of New Jersey, Nelson Biological Laboratories, 604 Allison Road, Piscataway, NJ 08854-8082, USA.

    The PDZ domains of postsynaptic density (PSD) protein-95 play a role in the localization of PSD-95 and binding partners to neuronal synapses. The identification of binding partners to these PDZ domains can help us in understanding how signalling complexes are assembled. We observed that one of the subunits in the sec6/8 or exocyst complex, sec8, contains a C-terminal consensus sequence for PDZ binding. Sec8 binds to PDZ1-2 of PSD-95, and this binding can be competed with a peptide that binds to PDZ1 and PDZ2 in the peptide-binding site. In addition, binding of sec8 is dependent on its C-terminal-binding sequence namely Thr-Thr-Val (TTV). Immunoblotting of rat tissue extracts shows that sec8 and PSD-95 are enriched in the same brain regions, and sec8 and PSD-95 have the same subcellular distribution in pheochromocytoma cells, suggesting that these proteins may interact in vivo. Immunoprecipitation studies of sec8 and PSD-95 in brain provide further evidence of a sec8 and PSD-95 interaction. Furthermore, the cytosolic PSD-95 interactor competes with sec8 for interaction with PSD-95. Taken together, our results suggest that the cytosolic PSD-95 interactor may function to regulate the ability of sec8 to bind to PSD-95.

    Funded by: NINDS NIH HHS: NS388892

    The Biochemical journal 2003;373;Pt 1;49-55

  • NMDA receptor trafficking through an interaction between PDZ proteins and the exocyst complex.

    Sans N, Prybylowski K, Petralia RS, Chang K, Wang YX, Racca C, Vicini S and Wenthold RJ

    Laboratory of Neurochemistry, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Building 50, Room 4146, 50 South Drive, Bethesda, MD 20892-8027, USA. sansn@nidcd.nih.gov

    NMDA (N-methyl-D-aspartate) receptors (NMDARs) are targeted to dendrites and anchored at the post-synaptic density (PSD) through interactions with PDZ proteins. However, little is known about how these receptors are sorted from the endoplasmic reticulum and Golgi apparatus to the synapse. Here, we find that synapse-associated protein 102 (SAP102) interacts with the PDZ-binding domain of Sec8, a member of the exocyst complex. Our results show that interactions between SAP102 and Sec8 are involved in the delivery of NMDARs to the cell surface in heterologous cells and neurons. Furthermore, they suggest that an exocyst-SAP102-NMDAR complex is an important component of NMDAR trafficking.

    Nature cell biology 2003;5;6;520-30

  • Human chromosome 7: DNA sequence and biology.

    Scherer SW, Cheung J, MacDonald JR, Osborne LR, Nakabayashi K, Herbrick JA, Carson AR, Parker-Katiraee L, Skaug J, Khaja R, Zhang J, Hudek AK, Li M, Haddad M, Duggan GE, Fernandez BA, Kanematsu E, Gentles S, Christopoulos CC, Choufani S, Kwasnicka D, Zheng XH, Lai Z, Nusskern D, Zhang Q, Gu Z, Lu F, Zeesman S, Nowaczyk MJ, Teshima I, Chitayat D, Shuman C, Weksberg R, Zackai EH, Grebe TA, Cox SR, Kirkpatrick SJ, Rahman N, Friedman JM, Heng HH, Pelicci PG, Lo-Coco F, Belloni E, Shaffer LG, Pober B, Morton CC, Gusella JF, Bruns GA, Korf BR, Quade BJ, Ligon AH, Ferguson H, Higgins AW, Leach NT, Herrick SR, Lemyre E, Farra CG, Kim HG, Summers AM, Gripp KW, Roberts W, Szatmari P, Winsor EJ, Grzeschik KH, Teebi A, Minassian BA, Kere J, Armengol L, Pujana MA, Estivill X, Wilson MD, Koop BF, Tosi S, Moore GE, Boright AP, Zlotorynski E, Kerem B, Kroisel PM, Petek E, Oscier DG, Mould SJ, Döhner H, Döhner K, Rommens JM, Vincent JB, Venter JC, Li PW, Mural RJ, Adams MD and Tsui LC

    Department of Genetics and Genomic Biology, The Hospital for Sick Children, Toronto, Ontario, Canada, M5G 1X8. steve@genet.sickkids.on.ca

    DNA sequence and annotation of the entire human chromosome 7, encompassing nearly 158 million nucleotides of DNA and 1917 gene structures, are presented. To generate a higher order description, additional structural features such as imprinted genes, fragile sites, and segmental duplications were integrated at the level of the DNA sequence with medical genetic data, including 440 chromosome rearrangement breakpoints associated with disease. This approach enabled the discovery of candidate genes for developmental diseases including autism.

    Funded by: Canadian Institutes of Health Research: 38103; NIGMS NIH HHS: P01 GM061354

    Science (New York, N.Y.) 2003;300;5620;767-72

  • The exocyst complex is required for targeting of Glut4 to the plasma membrane by insulin.

    Inoue M, Chang L, Hwang J, Chiang SH and Saltiel AR

    Life Sciences Institute, Departments of Internal Medicine and Physiology, University of Michigan Medical Center, Ann Arbor, Michigan 48109, USA.

    Insulin stimulates glucose transport by promoting exocytosis of the glucose transporter Glut4 (refs 1, 2). The dynamic processes involved in the trafficking of Glut4-containing vesicles, and in their targeting, docking and fusion at the plasma membrane, as well as the signalling processes that govern these events, are not well understood. We recently described tyrosine-phosphorylation events restricted to subdomains of the plasma membrane that result in activation of the G protein TC10 (refs 3, 4). Here we show that TC10 interacts with one of the components of the exocyst complex, Exo70. Exo70 translocates to the plasma membrane in response to insulin through the activation of TC10, where it assembles a multiprotein complex that includes Sec6 and Sec8. Overexpression of an Exo70 mutant blocked insulin-stimulated glucose uptake, but not the trafficking of Glut4 to the plasma membrane. However, this mutant did block the extracellular exposure of the Glut4 protein. So, the exocyst might have a crucial role in the targeting of the Glut4 vesicle to the plasma membrane, perhaps directing the vesicle to the precise site of fusion.

    Nature 2003;422;6932;629-33

  • The septin protein Nedd5 associates with both the exocyst complex and microtubules and disruption of its GTPase activity promotes aberrant neurite sprouting in PC12 cells.

    Vega IE and Hsu SC

    Department of Cell Biology and Neuroscience, Rutgers, Nelson Biological Laboratories, State University of New Jersey, Piscataway 08854, USA.

    Nedd5 is a septin protein enriched in brain and associates with the exocyst complex, a protein complex required for neurite outgrowth in neuroendocrine PC12 cells. In this study, we further investigate the association between Nedd5 and the exocyst complex as well as the role of Nedd5 in neurite outgrowth in differentiating PC12 cells. The endogenous Nedd5 is enriched at the perinuclear region in undifferentiated PC12 cells and radiates outward, from the perinuclear region toward the growth cone, upon NGF-induced PC12 neuronal differentiation. Nedd5, as well as other septin proteins, co-immunoprecipitates with the exocyst complex and tubulin from rat brain lysate. Interestingly, the over-expression of a GTPase-defective Nedd5 mutant promotes aberrant neurite sprouting in PC12 cells. These results demonstrate that Nedd5 and other septin proteins are associated with both the exocyst complex and microtubules and uncover a putative role for the Nedd5 GTPase activity in neurite outgrowth. Taken together, these findings suggest that Nedd5 may be required for polarized neurite outgrowth, perhaps, by facilitating the exocyst complex function during neuronal differentiation.

    Funded by: NIGMS NIH HHS: F31 GM020274, GM20274-01; NINDS NIH HHS: NS388892

    Neuroreport 2003;14;1;31-7

  • Ral-GTPase influences the regulation of the readily releasable pool of synaptic vesicles.

    Polzin A, Shipitsin M, Goi T, Feig LA and Turner TJ

    Department of Biochemistry, Tufts University School of Medicine, Tufts-New England Medical Center, Boston, MA 02111, USA.

    The Ral proteins are members of the Ras superfamily of GTPases. Because they reside in synaptic vesicles, we used transgenic mice expressing a dominant inhibitory form of Ral to investigate the role of Ral in neurosecretion. Using a synaptosomal secretion assay, we found that while K(+)-evoked secretion of glutamate was normal, protein kinase C-mediated enhancement of glutamate secretion was suppressed in the mutant mice. Since protein kinase C effects on secretion have been shown to be due to enhancement of the size of the readily releasable pool of synaptic vesicles docked at the plasma membrane, we directly measured the refilling of this readily releasable pool of synaptic vesicles after Ca(2+)-triggered exocytosis. Refilling of the readily releasable pool was suppressed in synaptosomes from mice expressing dominant inhibitory Ral. Moreover, we found that protein kinase C and calcium-induced phosphorylation of proteins thought to influence synaptic vesicle function, such as MARCKS, synapsin, and SNAP-25, were all reduced in synaptosomes from these transgenic mice. Concomitant with these studies, we searched for new functions of Ral by detecting proteins that specifically bind to it in cells. Consistent with the phenotype of the transgenic mice described above, we found that active but not inactive RalA binds to the Sec6/8 (exocyst) complex, whose yeast counterpart is essential for targeting exocytic vesicles to specific docking sites on the plasma membrane. These findings demonstrate a role for Ral-GTPase signaling in the modulation of the readily releasable pool of synaptic vesicles and suggest the possible involvement of Ral-Sec6/8 (exocyst) binding in modulation of synaptic strength.

    Molecular and cellular biology 2002;22;6;1714-22

  • The brain exocyst complex interacts with RalA in a GTP-dependent manner: identification of a novel mammalian Sec3 gene and a second Sec15 gene.

    Brymora A, Valova VA, Larsen MR, Roufogalis BD and Robinson PJ

    Children's Medical Research Institute, 214 Hawkesbury Road, Westmead NSW 2145, Australia.

    Ral is a small GTPase involved in critical cellular signaling pathways. The two isoforms, RalA and RalB, are widely distributed in different tissues, with RalA being enriched in brain. The best characterized RalA signaling pathways involve RalBP1 and phospholipase D. To investigate RalA signaling in neuronal cells we searched for RalA-binding proteins in brain. We found at least eight proteins that bound RalA in a GTP-dependent manner. Matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS) identified these as the components of the exocyst complex. The yeast exocyst is a regulator of polarized secretion, docking vesicles to regions of the plasma membrane involved in active exocytosis. We identified the human FLJ10893 protein as the mammalian homologue of the yeast exocyst protein Sec3p. The exocyst complex did not contain the previously identified exocyst component rSec15, but a new homologue of both yeast Sec15p and rSec15, called KIAA0919. Western blots confirmed that two rat exocyst proteins, rSec6 and rSec8, bound active RalA in nerve terminals, as did RalBP1. Phospholipase D bound RalA in a nucleotide-independent manner. This places the RalA signaling system in mammalian nerve terminals, where the exocyst may act as an effector for activated RalA in directing sites of exocytosis.

    The Journal of biological chemistry 2001;276;32;29792-7

  • Toward a catalog of human genes and proteins: sequencing and analysis of 500 novel complete protein coding human cDNAs.

    Wiemann S, Weil B, Wellenreuther R, Gassenhuber J, Glassl S, Ansorge W, Böcher M, Blöcker H, Bauersachs S, Blum H, Lauber J, Düsterhöft A, Beyer A, Köhrer K, Strack N, Mewes HW, Ottenwälder B, Obermaier B, Tampe J, Heubner D, Wambutt R, Korn B, Klein M and Poustka A

    Molecular Genome Analysis, German Cancer Research Center, 69120 Heidelberg, Germany. s.wiemann@dkfz.de

    With the complete human genomic sequence being unraveled, the focus will shift to gene identification and to the functional analysis of gene products. The generation of a set of cDNAs, both sequences and physical clones, which contains the complete and noninterrupted protein coding regions of all human genes will provide the indispensable tools for the systematic and comprehensive analysis of protein function to eventually understand the molecular basis of man. Here we report the sequencing and analysis of 500 novel human cDNAs containing the complete protein coding frame. Assignment to functional categories was possible for 52% (259) of the encoded proteins, the remaining fraction having no similarities with known proteins. By aligning the cDNA sequences with the sequences of the finished chromosomes 21 and 22 we identified a number of genes that either had been completely missed in the analysis of the genomic sequences or had been wrongly predicted. Three of these genes appear to be present in several copies. We conclude that full-length cDNA sequencing continues to be crucial also for the accurate identification of genes. The set of 500 novel cDNAs, and another 1000 full-coding cDNAs of known transcripts we have identified, adds up to cDNA representations covering 2%--5 % of all human genes. We thus substantially contribute to the generation of a gene catalog, consisting of both full-coding cDNA sequences and clones, which should be made freely available and will become an invaluable tool for detailed functional studies.

    Genome research 2001;11;3;422-35

  • Prediction of the coding sequences of unidentified human genes. XIX. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro.

    Nagase T, Kikuno R, Hattori A, Kondo Y, Okumura K and Ohara O

    Kazusa DNA Research Institute, Kisarazu, Chiba, Japan.

    As an extension of our human cDNA project for accumulating sequence information on the coding sequences of unidentified genes, we here present the entire sequences of 100 cDNA clones of unidentified genes, named KIAA1673-KIAA1772, from three sets of size-fractionated cDNA libraries derived from human adult whole brain, hippocampus, and fetal whole brain. The average sizes of the inserts and corresponding open reading frames of cDNA clones analyzed here were 4.9 kb and 2.7 kb (corresponding to 895 amino acid residues), respectively. By computer-assisted analysis of the deduced amino acid sequences, 44 predicted gene products were classified into five functional categories of proteins relating to cell signaling/communication, nucleic acid management, cell structure/motility, protein management, and metabolism. Furthermore, the expression profiles of the genes were also studied in 10 human tissues, 8 brain regions, spinal cord, fetal brain and fetal liver by reverse-transcription-coupled polymerase chain reaction, the products of which were quantified by enzyme-linked immunosorbent assay.

    DNA research : an international journal for rapid publication of reports on genes and genomes 2000;7;6;347-55

  • DNA cloning using in vitro site-specific recombination.

    Hartley JL, Temple GF and Brasch MA

    Life Technologies, Inc., Rockville, Maryland 20850, USA. jhartley@lifetech.com

    As a result of numerous genome sequencing projects, large numbers of candidate open reading frames are being identified, many of which have no known function. Analysis of these genes typically involves the transfer of DNA segments into a variety of vector backgrounds for protein expression and functional analysis. We describe a method called recombinational cloning that uses in vitro site-specific recombination to accomplish the directional cloning of PCR products and the subsequent automatic subcloning of the DNA segment into new vector backbones at high efficiency. Numerous DNA segments can be transferred in parallel into many different vector backgrounds, providing an approach to high-throughput, in-depth functional analysis of genes and rapid optimization of protein expression. The resulting subclones maintain orientation and reading frame register, allowing amino- and carboxy-terminal translation fusions to be generated. In this paper, we outline the concepts of this approach and provide several examples that highlight some of its potential.

    Genome research 2000;10;11;1788-95

  • Systematic subcellular localization of novel proteins identified by large-scale cDNA sequencing.

    Simpson JC, Wellenreuther R, Poustka A, Pepperkok R and Wiemann S

    Department of Cell Biology and Biophysics, EMBL Heidelberg, Germany.

    As a first step towards a more comprehensive functional characterization of cDNAs than bioinformatic analysis, which can only make functional predictions for about half of the cDNAs sequenced, we have developed and tested a strategy that allows their systematic and fast subcellular localization. We have used a novel cloning technology to rapidly generate N- and C-terminal green fluorescent protein fusions of cDNAs to examine the intracellular localizations of > 100 expressed fusion proteins in living cells. The entire analysis is suitable for automation, which will be important for scaling up throughput. For > 80% of these new proteins a clear intracellular localization to known structures or organelles could be determined. For the cDNAs where bioinformatic analyses were able to predict possible identities, the localization was able to support these predictions in 75% of cases. For those cDNAs where no homologies could be predicted, the localization data represent the first information.

    EMBO reports 2000;1;3;287-92

  • Subunit composition, protein interactions, and structures of the mammalian brain sec6/8 complex and septin filaments.

    Hsu SC, Hazuka CD, Roth R, Foletti DL, Heuser J and Scheller RH

    Howard Hughes Medical Institute, Department of Molecular and Cellular Physiology, Stanford University School of Medicine, California 94305, USA.

    Both the sec6/8 complex and septin filaments have been implicated in directing vesicles and proteins to sites of active membrane addition in yeast. The rat brain sec6/8 complex coimmunoprecipitates with a filament composed of four mammalian septins, suggesting an interaction between these complexes. One of the septins, CDC10, displays broad subcellular and tissue distributions and is found in postmitotic neurons as well as dividing cells. Electron microscopic studies showed that the purified rat brain septins form filaments of 8.25 nm in diameter; the lengths of the filaments are multiples of 25 nm. Glutaraldehyde-fixed rat brain sec6/8 complex adopts a conformation resembling the letter "T" or "Y". The sec6/8 and septin complexes likely play an important role in trafficking vesicles and organizing proteins at the plasma membrane of neurons.

    Neuron 1998;20;6;1111-22

  • Sec6/8 complex is recruited to cell-cell contacts and specifies transport vesicle delivery to the basal-lateral membrane in epithelial cells.

    Grindstaff KK, Yeaman C, Anandasabapathy N, Hsu SC, Rodriguez-Boulan E, Scheller RH and Nelson WJ

    Department of Molecular and Cellular Physiology, Stanford University School of Medicine, California 94305-5345, USA.

    In budding yeast, the Sec6/8p complex is essential for generating cell polarity by specifying vesicle delivery to the bud tip. We show that Sec6/8 homologs are components of a cytosolic, approximately 17S complex in nonpolarized MDCK epithelial cells. Upon initiation of calcium-dependent cell-cell adhesion, approximately 70% of Sec6/8 is rapidly (t(1/2) approximately 3-6 hr) recruited to sites of cell-cell contact. In streptolysin-O-permeabilized MDCK cells, Sec8 antibodies inhibit delivery of LDL receptor to the basal-lateral membrane, but not p75NTR to the apical membrane. These results indicate that lateral membrane recruitment of the Sec6/8 complex is a consequence of cell-cell adhesion and is essential for the biogenesis of epithelial cell surface polarity.

    Funded by: NIDDK NIH HHS: DK09368; NIGMS NIH HHS: GM34107, GM35527, R01 GM034107

    Cell 1998;93;5;731-40

  • Subunit structure of the mammalian exocyst complex.

    Kee Y, Yoo JS, Hazuka CD, Peterson KE, Hsu SC and Scheller RH

    Howard Hughes Medical Institute, Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford CA 94305-5428, USA.

    The exocyst is a protein complex required for the late stages of secretion in yeast. Unlike the SNAREs (SNAP receptors), important secretory proteins that are broadly distributed on the target membrane, the exocyst is specifically located at sites of vesicle fusion. We have isolated cDNAs encoding the rexo70, rsec5, and rsec15 subunits of the mammalian complex. The amino acid sequences encoded by these genes are between 21% and 24% identical to their yeast homologs. All three genes are broadly expressed and multiple transcripts are observed for rexo70 and rsec15. Characterization of cDNAs encoding the 84-kDa subunit of the mammalian complex revealed a novel protein. mAbs were generated to the mammalian rsec6 subunit of the exocyst complex. rsec6 immunoreactivity is found in a punctate distribution at terminals of PC12 cell processes at or near sites of granule exocytosis.

    Proceedings of the National Academy of Sciences of the United States of America 1997;94;26;14438-43

Gene lists (6)

Gene List Source Species Name Description Gene count
L00000009 G2C Homo sapiens Human PSD Human orthologues of mouse PSD adapted from Collins et al (2006) 1080
L00000016 G2C Homo sapiens Human PSP Human orthologues of mouse PSP adapted from Collins et al (2006) 1121
L00000059 G2C Homo sapiens BAYES-COLLINS-HUMAN-PSD-CONSENSUS Human cortex PSD consensus 748
L00000061 G2C Homo sapiens BAYES-COLLINS-MOUSE-PSD-CONSENSUS Mouse cortex PSD consensus (ortho) 984
L00000069 G2C Homo sapiens BAYES-COLLINS-HUMAN-PSD-FULL Human cortex biopsy PSD full list 1461
L00000071 G2C Homo sapiens BAYES-COLLINS-MOUSE-PSD-FULL Mouse cortex PSD full list (ortho) 1556
© G2C 2014. The Genes to Cognition Programme received funding from The Wellcome Trust and the EU FP7 Framework Programmes:
EUROSPIN (FP7-HEALTH-241498), SynSys (FP7-HEALTH-242167) and GENCODYS (FP7-HEALTH-241995).

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