- Open Access
PhenoFam-gene set enrichment analysis through protein structural information
© Paszkowski-Rogacz et al; licensee BioMed Central Ltd. 2010
Received: 23 February 2010
Accepted: 17 May 2010
Published: 17 May 2010
With the current technological advances in high-throughput biology, the necessity to develop tools that help to analyse the massive amount of data being generated is evident. A powerful method of inspecting large-scale data sets is gene set enrichment analysis (GSEA) and investigation of protein structural features can guide determining the function of individual genes. However, a convenient tool that combines these two features to aid in high-throughput data analysis has not been developed yet. In order to fill this niche, we developed the user-friendly, web-based application, PhenoFam.
PhenoFam performs gene set enrichment analysis by employing structural and functional information on families of protein domains as annotation terms. Our tool is designed to analyse complete sets of results from quantitative high-throughput studies (gene expression microarrays, functional RNAi screens, etc.) without prior pre-filtering or hits-selection steps. PhenoFam utilizes Ensembl databases to link a list of user-provided identifiers with protein features from the InterPro database, and assesses whether results associated with individual domains differ significantly from the overall population. To demonstrate the utility of PhenoFam we analysed a genome-wide RNA interference screen and discovered a novel function of plexins containing the cytoplasmic RasGAP domain. Furthermore, a PhenoFam analysis of breast cancer gene expression profiles revealed a link between breast carcinoma and altered expression of PX domain containing proteins.
PhenoFam provides a user-friendly, easily accessible web interface to perform GSEA based on high-throughput data sets and structural-functional protein information, and therefore aids in functional annotation of genes.
Analysis of large sets of results derived from high-throughput experiments is a challenging but promising field of study. Enrichment analysis is a very powerful strategy helping researchers in identifying biological processes or pathways related to their studies. Most of the currently available tools (i.e. Onto-Express , DAVID , FatiGO+ , ConceptGene  and others reviewed in ) search for enrichment of Gene Ontology (GO) terms , KEGG pathways  or other functional properties in a pre-selected subset of genes by contrasting it with the background set, usually a whole genome. This approach strongly relies on a chosen hit selection algorithm and user-defined thresholds. Moreover, the experimental results (i.e. level of expression or phenotype strength) are not considered. There are few applications overcoming these limitations by performing gene set enrichment analysis (GSEA) . They search for gene annotations enriched on the top or the bottom of a complete list of genes ranked by their experimental values. This allows even mild effects to contribute to the overall enrichment score. However, to our knowledge, annotations used by available GSEA tools have so far primarily been used in combination with GO terms, pathways or transcription factors, and only few of these applications are web-based (e.g. GSEA , FatiScan , GeneTrail ).
In recent years, access to high-resolution protein structural information has increased considerably. Many new structures reveal the presence of domains known from other proteins, and the domain composition of a protein can help forming a hypothesis about its biological function (e.g. a homeodomain fold indicates a transcription factor activity involved in cellular differentiation ). Moreover, Hahne et al. demonstrated, that the domain composition of proteins could be used for predicting their pathway membership . There are many databases classifying and providing information about protein families, domains, regions and functionally relevant sites. InterPro  constitutes a repository that integrates a number of the most well established sources of data: PROSITE , HAMAP , Pfam , PRINTS , ProDom , SMART , TIGRFAMs , PIRSF , SUPERFAMILY , Gene3D  and PANTHER . We have developed a GSEA web application that can be used for analysing data from large-scale experiments (phenotypes, gene expression, etc.). Our tool combines the experimental results with annotations from the databases integrated in InterPro (called 'member databases'), thereby allowing a streamlined structure/function annotation of proteins. Utilization of information about protein domain families in GSEA is a novel approach that can be used in parallel to other enrichment analysis applications.
PhenoFam is a Java web application running on a Tomcat 5.5 server. It uses a MySQL database to store mappings between various protein, gene or probe names and identifiers related to member databases of InterPro. This database is an easily updatable compilation of the current releases of the Ensembl database . Client-server communication is mainly handled by AJAX technologies. User-uploaded data sets and calculation results are stored as session objects on the server side for at least 30 minutes after closing the browser window.
It must be noted that all identifier mappings are based on contents of the Ensembl database, which establishes the links based on sequence similarity of entities stored in remote databases to sequences stored in Ensembl. This approach provides the highest quality of associations. However, care must be taken if gene-related identifiers are used. Due to alternative splicing, different gene products may be composed of different protein domains or even encode different proteins (i.e. shift in the reading frame). In such cases, a value associated with the user-provided identifier is mapped to all possible protein features that can be associated with the gene (Figure 1).
Gene set enrichment analysis
To test if a set of values associated with a given domain is significantly higher or lower than the remaining set of values, we use the Mann-Whitney U-test. The U-test is the most powerful nonparametric alternative to the Student's t-test. Its main advantage is that it makes no assumptions about the underlying distributions and is more robust in case of outliers. The U-test is also implemented in other popular GSEA tools, i.e. GeneTrail  or PANTHER [26, 27]. Other applications (i.e. GOdist , GSEA ) implemented the Kolmogorov-Smirnov (KS) test, another non-parametric procedure that checks whether two samples (values associated with a given domain and the other values) may be assumed to come from the same distribution. However, the KS test is also sensitive to differences in the general shapes of the distributions, which limits its use for our PhenoFam application. Parametric analysis, which was proposed by Kim et al. and implemented in PAGE , is also not suitable for GSEA of protein domains because many domains are associated with small number of proteins (< 10). In those cases, the normality criteria required for parametric tests might not be satisfied. Adjustment for multiple testing is done using the false discovery rate (FDR) control procedure designed by Benjamini and Hochberg  and resulting q-values are obtained by applying Storey's algorithm [31, 32]. Additionally, we calculate a Herrnstein's ρ statistic , which is an unbiased measure of the overlap between distributions of values in the two compared sets. It can reach values between 0 and 1, where 0.5 indicates a complete overlap of the two distributions and both extreme values show a complete separation. This statistic shows how much a median of domain-associated values differs from a median of the other values, and together with the p-value can help identifying domains of interest. We recommend using it for sorting results that passed the significance-threshold criteria. Due to the fact that InterPro is a collection of partially redundant databases, the enrichment analysis and the adjustment for multiple testing procedure are performed for each database independently. Otherwise, treating InterPro as a uniform set of annotations would lead to a significant underestimation of the results.
To implement the user interface and to ensure compatibility with all major browsers, we used the Google Web Toolkit (GWT) framework. We have designed a simple and user-friendly data management system for storing uploaded data sets and the analysis results. It allows users to investigate and compare multiple data sets at the same time.
PhenoFam allows many data sets as the starting point, such as results of microarray studies, systematic RNA interference (RNAi) screens, ChIP-Chip/ChIP-Seq experiments or comparative mass-spectrometry (i.e. SILAC) results. To test the utility of PhenoFam, we analysed a data-set derived from a genome-scale cell cycle progression RNAi screen . In this screen, a genome-wide study of genes was carried out providing z-scores for cell cycle progression phenotypes (i.e. cells in G1, S, G2/M phases and polyploidy) for each knockdown.
Normalized values of polyploidy RNAi phenotypes of plexins, from the primary cell cycle progression screen.
Moreover, based on this result we predicted that knockdown of the gene PLXNB3, which belongs to the same family, but had not been tested in the screen, would also increase the degree of polyploidy. Indeed, an increased number of polyploid cells were measured after PLXNB3 knockdown (Figure 3), indicating that depletion of this gene, like other plexins with cytoplasmic RasGAP domains, influences proper cytokinesis. This example demonstrates that PhenoFam can be a valuable support for selecting hits from the RNAi screens.
To show that PhenoFam is also suitable for analysis of other large-scale data-sets, we examined publicly available gene expression data that compares transcriptomes of human breast carcinoma and healthy tissue . GSEA of this data-set using GeneTrail  showed that genes whose expression is altered in breast cancer are significantly enriched with the 'signal transduction' and 'cell differentiation' gene ontologies, highliting the importance of these biological processes during cellular transformation (data not shown). However, the analysis with GeneTrail did not provide information of enrichment of certain protein domains. In contrast, analysis of the same data-set with PhenoFam showed that among differentially expressed genes, Ras-family proteins and phox (PX) domain-containing proteins were enriched (p < 0.001, data not shown).
Ras GTPases are known to play a role in breast cancer development  and, therefore, it is not surprising that this group of proteins was enriched in this set. Proteins containing a PX domain are involved in cell signalling, vesicular trafficking, protein sorting and lipid modification, and are primarily found in sorting nexins . Previous studies suggest that various sorting nexins are involved in leukemia , colon tumorigenesis  and, in general, contribute to cell cycle progression in mammalian cells . However, their role in breast cancer has not been described so far. Our PhenoFam anaysis suggests that proteins with PX domains are frequently misregulated in breast cancer. Hence, we propose that these proteins should be investigated for a possible role in breast cancer development.
PhenoFam is a computational tool designed to analyse experimental results by integration of functional and structural information about protein families. The distinct features of our application include a user-friendly interface and a broad range of supported genomes and identifiers. It should also be noted that our algorithm, in contrast to existing software, treats the InterPro repository as a collection of partially redundant databases, which improves the power of our testing procedure. Using a specific example, we show that the application can be used as an additional hit selection tool for functional screens. Typical hit selection procedures (i.e. z-score or quantile-based normalization) apply thresholds that can be passed only by genes showing the strongest phenotypes, which often leads to a high false-negatives rate. In case of our GSEA method, a domain may appear to be significantly enriched despite moderate phenotypes of the associated genes. From the potential relationship between the domain and the investigated biological process, genes with moderate phenotypic scores are considered in the list of hits selected from the screen, thereby reducing the false-negative rate.
We also demonstrated that PhenoFam can help forming novel hypothesis based on gene expression data. Accordingly, PhenoFam should be useful in analysing results of other high-throughput experiments, such as ChiP-Chip/ChiP-Seq and comparative mass-spectrometry. In summary, together with other enrichment analysis tools, PhenoFam can assist in annotating genes of unknown function and in discovering new functions of already characterised genes.
Availability and requirements
Project name: PhenoFam
Project homepage: http://www.phenofam.org/
Operating system(s): Platform independent (web-based application)
Programming language: Java
License: GNU GPLv3 http://www.gnu.org/licenses/gpl-3.0.html
Any restrictions to use by non-academics: None
This work was supported by the Max Planck Society, the Bundesministerium für Bildung und Forschung grant NGFN-Plus (01GS0859), the Deutsche Forschungsgemeinschaft (SFB 655 'Cells into tissues') and by the Klaus Tschira Stiftung gGmbH.
- Khatri P, Draghici S, Ostermeier GC, Krawetz SA: Profiling gene expression using onto-express. Genomics 2002, 79(2):266–70. 10.1006/geno.2002.6698View ArticlePubMedGoogle Scholar
- Dennis G, Sherman BT, Hosack Da, Yang J, Gao W, Lane HC, Lempicki Ra: DAVID: Database for Annotation, Visualization, and Integrated Discovery. Genome biology 2003, 4(5):P3. 10.1186/gb-2003-4-5-p3View ArticlePubMedGoogle Scholar
- Al-Shahrour F, Minguez P, Tarraga J, Medina I, Alloza E, Montaner D, Dopazo J: FatiGO +: a functional profiling tool for genomic data. Integration of functional annotation, regulatory motifs and interaction data with microarray experiments. Nucleic acids research 2007, (35 Web Server):W91–6. 10.1093/nar/gkm260Google Scholar
- Sartor MA, Mahavisno V, Keshamouni VG, Cavalcoli J, Wright Z, Karnovsky A, Kuick R, Jagadish HV, Mirel B, Weymouth T, Athey B, Omenn GS: ConceptGen: a gene set enrichment and gene set relation mapping tool. Bioinformatics (Oxford, England) 2010, 26(4):456–63. 10.1093/bioinformatics/btp683View ArticleGoogle Scholar
- Huang daW, Sherman BT, Lempicki RA: Bioinformatics enrichment tools: paths toward the comprehensive functional analysis of large gene lists. Nucleic Acids Res 2009, 37: 1–13. 10.1093/nar/gkn923View ArticlePubMed CentralGoogle Scholar
- Ashburner M, Ball CA, Blake JA, Botstein D, Butler H, Cherry JM, Davis AP, Dolinski K, Dwight SS, Eppig JT, Harris MA, Hill DP, Issel-Tarver L, Kasarskis A, Lewis S, Matese JC, Richardson JE, Ringwald M, Rubin GM, Sherlock G: Gene ontology: tool for the unification of biology. The Gene Ontology Consortium. Nat Genet 2000, 25: 25–29. 10.1038/75556View ArticlePubMedPubMed CentralGoogle Scholar
- Kanehisa M, Goto S, Furumichi M, Tanabe M, Hirakawa M: KEGG for representation and analysis of molecular networks involving diseases and drugs. Nucleic acids research 2010, (38 Database):D355–60. 10.1093/nar/gkp896Google Scholar
- Mootha VK, Lindgren CM, Eriksson KF, Subramanian A, Sihag S, Lehar J, Puigserver P, Carlsson E, Ridderstrråle M, Laurila E, Houstis N, Daly MJ, Patterson N, Mesirov JP, Golub TR, Tamayo P, Spiegelman B, Lander ES, Hirschhorn JN, Altshuler D, Groop LC: PGC-1alpha-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes. Nat Genet 2003, 34: 267–273. 10.1038/ng1180View ArticlePubMedGoogle Scholar
- Subramanian A, Tamayo P, Mootha VK, Mukherjee S, Ebert BL, Gillette MA, Paulovich A, Pomeroy SL, Golub TR, Lander ES, Mesirov JP: Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profiles. Proceedings of the National Academy of Sciences of the United States of America 2005, 102(43):15545–15550. 10.1073/pnas.0506580102View ArticlePubMedPubMed CentralGoogle Scholar
- Keller A, Backes C, Al-Awadhi M, Gerasch A, Küntzer J, Kohlbacher O, Kaufmann M, Lenhof HP: GeneTrailExpress: a web-based pipeline for the statistical evaluation of microarray experiments. BMC bioinformatics 2008, 9: 552. 10.1186/1471-2105-9-552View ArticlePubMedPubMed CentralGoogle Scholar
- Gehring WJ, Qian YQ, Billeter M, Furukubo-Tokunaga K, Schier AF, Resendez-Perez D, Affolter M, Otting G, Wöthrich K: Homeodomain-DNA recognition. Cell 1994, 78: 211–223. 10.1016/0092-8674(94)90292-5View ArticlePubMedGoogle Scholar
- Hahne F, Mehrle A, Arlt D, Poustka A, Wiemann S, Beissbarth T: Extending pathways based on gene lists using InterPro domain signatures. BMC bioinformatics 2008, 9: 3. 10.1186/1471-2105-9-3View ArticlePubMedPubMed CentralGoogle Scholar
- Hunter S, Apweiler R, Attwood TK, Bairoch A, Bateman A, Binns D, Bork P, Das U, Daugherty L, Duquenne L, Finn RD, Gough J, Haft D, Hulo N, Kahn D, Kelly E, Laugraud A, Letunic I, Lonsdale D, Lopez R, Madera M, Maslen J, McAnulla C, McDowall J, Mistry J, Mitchell A, Mulder N, Natale D, Orengo C, Quinn AF, Selengut JD, Sigrist CJA, Thimma M, Thomas PD, Valentin F, Wilson D, Wu CH, Yeats C: InterPro: the integrative protein signature database. Nucleic acids research 2009, (37 Database):D211–5. 10.1093/nar/gkn785Google Scholar
- Hulo N, Bairoch A, Bulliard V, Cerutti L, Cuche BA, de Castro E, Lachaize C, Langendijk-Genevaux PS, Sigrist CJA: The 20 years of PROSITE. Nucleic acids research 2008, (36 Database):D245–9.Google Scholar
- Lima T, Auchincloss AH, Coudert E, Keller G, Michoud K, Rivoire C, Bulliard V, de Castro E, Lachaize C, Baratin D, Phan I, Bougueleret L, Bairoch A: HAMAP: a database of completely sequenced microbial proteome sets and manually curated microbial protein families in UniProtKB/Swiss-Prot. Nucleic acids research 2009, (37 Database):D471–8. 10.1093/nar/gkn661Google Scholar
- Finn RD, Tate J, Mistry J, Coggill PC, Sammut SJ, Hotz HR, Ceric G, Forslund K, Eddy SR, Sonnhammer EL, Bateman A: The Pfam protein families database. Nucleic Acids Res 2008, 36: D281–288. 10.1093/nar/gkm960View ArticlePubMedPubMed CentralGoogle Scholar
- Attwood TK, Bradley P, Flower DR, Gaulton A, Maudling N, Mitchell AL, Moulton G, Nordle A, Paine K, Taylor P, Uddin A, Zygouri C: PRINTS and its automatic supplement, prePRINTS. Nucleic acids research 2003, 31: 400–2. 10.1093/nar/gkg030View ArticlePubMedPubMed CentralGoogle Scholar
- Corpet F, Servant F, Gouzy J, Kahn D: ProDom and ProDom-CG: tools for protein domain analysis and whole genome comparisons. Nucleic acids research 2000, 28: 267–9. 10.1093/nar/28.1.267View ArticlePubMedPubMed CentralGoogle Scholar
- Letunic I, Goodstadt L, Dickens NJ, Doerks T, Schultz J, Mott R, Ciccarelli F, Copley RR, Ponting CP, Bork P: Recent improvements to the SMART domain-based sequence annotation resource. Nucleic acids research 2002, 30: 242–4. 10.1093/nar/30.1.242View ArticlePubMedPubMed CentralGoogle Scholar
- Haft DH, Selengut JD, White O: The TIGRFAMs database of protein families. Nucleic acids research 2003, 31: 371–3. 10.1093/nar/gkg128View ArticlePubMedPubMed CentralGoogle Scholar
- Wu CH, Yeh LSL, Huang H, Arminski L, Castro-Alvear J, Chen Y, Hu Z, Kourtesis P, Ledley RS, Suzek BE, Vinayaka CR, Zhang J, Barker WC: The Protein Information Resource. Nucleic acids research 2003, 31: 345–7. 10.1093/nar/gkg040View ArticlePubMedPubMed CentralGoogle Scholar
- Gough J, Karplus K, Hughey R, Chothia C: Assignment of homology to genome sequences using a library of hidden Markov models that represent all proteins of known structure. Journal of molecular biology 2001, 313(4):903–19. 10.1006/jmbi.2001.5080View ArticlePubMedGoogle Scholar
- Pearl F, Todd A, Sillitoe I, Dibley M, Redfern O, Lewis T, Bennett C, Marsden R, Grant A, Lee D, Akpor A, Maibaum M, Harrison A, Dallman T, Reeves G, Diboun I, Addou S, Lise S, Johnston C, Sillero A, Thornton J, Orengo C: The CATH Domain Structure Database and related resources Gene3D and DHS provide comprehensive domain family information for genome analysis. Nucleic acids research 2005, (33 Database):D247–51.Google Scholar
- Mi H, Lazareva-Ulitsky B, Loo R, Kejariwal A, Vandergriff J, Rabkin S, Guo N, Muruganujan A, Doremieux O, Campbell MJ, Kitano H, Thomas PD: The PANTHER database of protein families, subfamilies, functions and pathways. Nucleic acids research 2005, (33 Database):D284–8.Google Scholar
- Hubbard TJ, Aken BL, Ayling S, Ballester B, Beal K, Bragin E, Brent S, Chen Y, Clapham P, Clarke L, Coates G, Fairley S, Fitzgerald S, Fernandez-Banet J, Gordon L, Graf S, Haider S, Hammond M, Holland R, Howe K, Jenkinson A, Johnson N, Kahari A, Keefe D, Keenan S, Kinsella R, Kokocinski F, Kulesha E, Lawson D, Longden I, Megy K, Meidl P, Overduin B, Parker A, Pritchard B, Rios D, Schuster M, Slater G, Smedley D, Spooner W, Spudich G, Trevanion S, Vilella A, Vogel J, White S, Wilder S, Zadissa A, Birney E, Cunningham F, Curwen V, Durbin R, Fernandez-Suarez XM, Herrero J, Kasprzyk A, Proctor G, Smith J, Searle S, Flicek P: Ensembl 2009. Nucleic Acids Res 2009, 37: D690–697. 10.1093/nar/gkn828View ArticlePubMedPubMed CentralGoogle Scholar
- Thomas PD, Campbell MJ, Kejariwal A, Mi H, Karlak B, Daverman R, Diemer K, Muruganujan A, Narechania A: PANTHER: a library of protein families and subfamilies indexed by function. Genome research 2003, 13(9):2129–41. 10.1101/gr.772403View ArticlePubMedPubMed CentralGoogle Scholar
- Thomas PD, Kejariwal A, Guo N, Mi H, Campbell MJ, Muruganujan A, Lazareva-Ulitsky B: Applications for protein sequence-function evolution data: mRNA/protein expression analysis and coding SNP scoring tools. Nucleic Acids Research 2006, (34 Web Server):W645-W650. 10.1093/nar/gkl229Google Scholar
- Ben-Shaul Y, Bergman H, Soreq H: Identifying subtle interrelated changes in functional gene categories using continuous measures of gene expression. Bioinformatics (Oxford, England) 2005, 21(7):1129–37. 10.1093/bioinformatics/bti149View ArticleGoogle Scholar
- Kim SY, Volsky D: PAGE: parametric analysis of gene set enrichment. BMC bioinformatics 2005, 6: 144. 10.1186/1471-2105-6-144View ArticlePubMedPubMed CentralGoogle Scholar
- Benjamini Y, Hochberg Y: Controlling the False Discovery Rate - a Practical and Powerful Approach to Multiple Testing. Journal of the Royal Statistical Society Series B-Methodological 1995, 57: 289–300.Google Scholar
- Storey JD: A direct approach to false discovery rates. Journal of the Royal Statistical Society: Series B (Statistical Methodology) 2002, 64(3):479–498. 10.1111/1467-9868.00346View ArticleGoogle Scholar
- Storey JD, Tibshirani R: Statistical significance for genomewide studies. Proceedings of the National Academy of Sciences of the United States of America 2003, 100(16):9440–5. 10.1073/pnas.1530509100View ArticlePubMedPubMed CentralGoogle Scholar
- Hernstein RJ, Loveland DH, Cable C: Natural concepts in pigeons. J Exp Psychol Anim Behav Process 1976, 2: 285–302. 10.1037/0097-7403.2.4.285View ArticlePubMedGoogle Scholar
- Kittler R, Pelletier L, Heninger AK, Slabicki M, Theis M, Miroslaw L, Poser I, Lawo S, Grabner H, Kozak K, Wagner J, Surendranath V, Richter C, Bowen W, Jackson AL, Habermann B, Hyman AA, Buchholz F: Genome-scale RNAi profiling of cell division in human tissue culture cells. Nat Cell Biol 2007, 9: 1401–1412. 10.1038/ncb1659View ArticlePubMedGoogle Scholar
- Cheng ASL, Culhane AC, Chan MWY, Venkataramu CR, Ehrich M, Nasir A, Rodriguez BAT, Liu J, Yan PS, Quackenbush J, Nephew KP, Yeatman TJ, Huang THM: Epithelial progeny of estrogen-exposed breast progenitor cells display a cancer-like methylome. Cancer research 2008, 68(6):1786–96. 10.1158/0008-5472.CAN-07-5547View ArticlePubMedPubMed CentralGoogle Scholar
- Li T, Sparano JA: Inhibiting Ras signaling in the therapy of breast cancer. Clinical breast cancer 2003, 3(6):405–16. discussion 417–20 discussion 417-20 10.3816/CBC.2003.n.005View ArticlePubMedGoogle Scholar
- Worby CA, Dixon JE: Sorting out the cellular functions of sorting nexins. Nature reviews. Molecular cell biology 2002, 3(12):919–31. 10.1038/nrm974View ArticlePubMedGoogle Scholar
- Fuchs U, Rehkamp G, Haas OA, Slany R, Kōnig M, Bojesen S, Bohle RM, Damm-Welk C, Ludwig WD, Harbott J, Borkhardt A: The human formin-binding protein 17 (FBP17) interacts with sorting nexin, SNX2, and is an MLL-fusion partner in acute myelogeneous leukemia. Proceedings of the National Academy of Sciences of the United States of America 2001, 98(15):8756–61. 10.1073/pnas.121433898View ArticlePubMedPubMed CentralGoogle Scholar
- Nguyen LN, Holdren MS, Nguyen AP, Furuya MH, Bianchini M, Levy E, Mordoh J, Liu A, Guncay GD, Campbell JS, Parks WT: Sorting nexin 1 down-regulation promotes colon tumorigenesis. Clinical cancer research: an official journal of the American Association for Cancer Research 2006, 12(23):6952–9.View ArticleGoogle Scholar
- Fuster JJ, González JM, Edo MD, Viana R, Boya P, Cervera J, Verges M, Rivera J, Andrés V: Tumor suppressor p27Kip1 undergoes endolysosomal degradation through its interaction with sorting nexin 6. The FASEB journal: official publication of the Federation of American Societies for Experimental Biology 2010. E-pub E-pubGoogle Scholar
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.