Paul W. Sternberg
WormBook (online book about C. elegans and other nematodes)
Nematode Systems Biology
We seek to understand how a genome controls development, behavior and physiology. We use C. elegans molecular genetics to understand detailed mechanisms, and functional genomics to obtain global views of development and behavior. We tightly couple computation and experimental data, in part to use computation to make experimental tests more efficient. Moreover, we study other genomes, genetics, and biology of other nematodes to help us comprehend C. elegans, to learn how development and behavior evolve, and to learn how to control parasitic and pestilent nematodes.
Our efforts in genomics are experimental and computational. We worked with Caltech's Millard and Muriel Jacobs Genetics and Genome Laboratory to determine the genomic sequence of several nematode species using only short sequencing reads. The first was a new Caenorhabditis species (angaria) that is an outgroup for the five existing sequenced species of this genus. We used cDNA sequence data to help assemble larger than gene-size pieces of this genome. By comparing the C. angaria genome to other Caenorhabditis species, we identified thousands of short, high conserved sequences that we hypothesis are regulatory. In addition, we have sequenced, assembled and annotated the genome of Steinernema carpocapsae, an insect-killing nematode that can jump onto hosts (see below) and four other Steinernema species. We are also helping to sequence and analyze the genome and transcriptomes of the sheep parasite Haemonchus contortus and related animal parasites. For comparison we are analyzing genomes of several other free-living nematodes, including Panagrellus redivivus.
Our behavioral studies focused this year on sexual attraction, sleep, and host finding by parasitic nematodes. We have continued to study the chemicals (ascarosides) that constitute mating pheromone made by hermaphrodites (morphologically females but that make sperm for internal self-fertilization) and sensed by males. We hypothesize that ascarosides are a diverse family of nematode signaling molecules. To test this hypothesis we are continuing our collaboration with the labs of Art Edison and Frank Schroeder to purify mating cues from other nematode species. To study parasite behaviors, we are using three genera of insect killing nematodes that are used in insect biocontrol because they deliver toxic bacteria to their hosts. One key discovery this year is that Heterorhabditis bacteriophora and Steinernema carpocapsae use the same sensory neuron as C. elegans to respond to carbon dioxide. Steinernema carpocapsae is able to jump onto insects, and we are trying to understand the genetic and cellular basis for this amazing behavior, as well as its evolutionary origin, as only members of this genus can jump.
We have used channel rhodopsin to faithfully activate a neuron, as evidenced by whole-cell patch electrophysiology neuronal activity in a pre-synaptic cell expressing channel rhodopsin and then in its post-synaptic partner. Now that this system is validated, we are expressing channel rhodopsin and a genetically-encoded calcium sensor in a range of specific neurons to be able to examine neuronal circuit properties.
The infective juveniles (IJs) of H. bacteriophora and S. carpocapsae are analogous to the dauer larvae of C. elegans. Developing C. elegans larvae choose between proceeding directly to reproductive development or to arrest development as dauer larvae, depending on population density (signaled by several ascarosides) and the amount of food available. We are studying how larvae make this all-or-none decision. As worms exit the dauer stage they resume reproductive development and we have analyzed how the organization of genes into operon might facilitate a rapid transition to growth.
In the area of cell regulation, we have continued to study WNT and EGF signaling to define new components, how these two pathways interact, and what determines the specific outcomes of common signals. For this study we focus on the C. elegans vulva, a paradigm for analyzing organogenesis. In one project, we are using the polarity of the vulval secondary lineage to study how multiple types of WNT receptors act in concert or antagonistically. This year we discovered that fibroblast growth factor (FGF) signaling works with WNT in this process. EGF controls development via the RAS/MAPkinase pathway and behavior via phospholipase C-gamma pathway. We had previously found that the EGF-receptor acts in a single neuron, ALA, to control a sleep-like state. We are testing other conserved signaling pathways for common roles in sleep regulation, and using calcium imaging to examine neuronal function during worm sleep. We had discovered that a network of three homeoboxcontaining transcriptional regulatory proteins regulate expression of the EGF-receptor and other genes in the ALA neuron, and are now defining the cis-regulatory elements that respond to these homeobox proteins.
We are trying to learn how to efficiently define cis-regulatory elements using functional assays. We have established establishing pipelines for cis-regulatory computational analysis to define genomic elements that we test in transgenic C. elegans. For example, we tested some of our methods on elements that direct expression in the DVA neuron, which we had previously shown to control the extent of body flexion during locomotion.
We are developing new assays for regulatory elements. For a number of projects, we want to identify all the genes that are expressed in a particular cell at a particular time. We thus are trying different methods of obtaining a transcriptional profile from a single cell; the male linker cell is our first test case.
We started a new project on cell migration to understand both normal organogenesis and potential migratory programs that might be accessed by metastatic tumor cells. The C. elegans male linker cell (LC) undergoes a complex migration with changes in direction, speed, and morphology. An initial functional screen for genes involved in LC migration identified the Tlx ortholog nhr-67 as being necessary for the middle parts of the migratory program, such as negative regulation of the netrin receptor unc-5 to allow a ventral turn. We have profiled the transcriptome of individual LCs by microdissection, amplification, and cDNA deep sequencing. This study identified about 800 LC-enriched genes whose functions we are now analyzing, including a number of conserved proteins of unknown function that we predict will have roles in migration in human cells.
We examined several molecular aspects of nematode life-cycle decisions. We used L1 larval arrest to study nutritional control of these decisions, and went on to use microarrays and NanoString technology to examine transcriptional changes. We were early adopters of chromatin immunoprecipitation analyzed by deep sequencing (ChIP-seq) and discovered that RNA polymerase accumulates at the 5' end of transcriptional units during L1 arrest. We then examined the genomic organization related to arrested states and the transition back to growth. We used this analysis to develop a model for the selective advantage of operons in metazoans, namely that operons decrease the need for transcriptional resources in the initial stages of transition to growth, either release from L1 arrest or recovery from dauer larvae. We are now examining how the entry into dauer is controlled by dauer pheromones (mixture of ascarosides) and steroid hormones (dafachronic acid). We collaborated with Adam Anteb (Max-Planck-Institute for Biology of Ageing) to analyze the role of dafachronic acid in pheromone response, in particular how worms respond to a shift form high to low pheromones when larvae are deciding to undergo reproductive or dauer development.
We continue to organize, store, and display information about C. elegans and to extend these efforts to other nematodes. With our international team of collaborators, we present this information in an Internet-accessible database, WormBase. Our major contribution is to extract information from the literature, focusing on gene, protein, and cell function; gene expression; gene-gene interactions; and functional genomics data. Annotation of gene function includes use of the Gene Ontology (GO); and we are developing these ontologies as part of the GO Consortium. To facilitate these processes, we have developed Textpresso, a search engine for biological literature. In collaboration with other model organism databases, we have applied Textpresso to the literature of C. elegans, Drosophila, Arabidopsis, mouse, and zebrafish. We use this system to automate some steps in the extraction of information from full-text papers. We are working to extend Textpresso to human disease literature . Lastly, we are exploring ways of visualizing biological information.
Yu, H., Aleman-Meza, B., Gharib, S., Labocha, M.K., Cronin, C.J., Sternberg, P.W., Zhong, W. Systematic profiling of Caenorhabditis elegans locomotive behaviors reveals additional components in G-protein Gαq signaling. Proc Natl Acad Sci U S A. 110(29):11940-11945 PMID: 23818641.
Schwarz, E. M., Kato, M. and Sternberg, P. W. (2012). Functional transcriptomics of a migrating cell in Caenorhabditis elegans. Proc Natl. Acad. USA, (40):16246-51. doi: 10.1073/pnas.1203045109.
Schaedel, O. N., Gerisch, B., Antebi, A., and Sternberg, P.W. (2012). Hormonal signal amplification mediates environmental conditions during development and controls an irreversible commitment to adulthood. PLoS Biol. 2012 Apr;10(4):e1001306. Epub 2012 Apr 10. PMID: 22505848
Zhong, W. and Sternberg, P.W. (2006). Genome-wide prediction of C. elegans genetic interactions. Science 311: 1481-1484.
Rakowski, F., Srinivasan, J., Sternberg, P. W., Karbowski, J. (2013). Synaptic polarity of the interneuron circuit controlling C. elegans locomotion. Front. Neurosci. 7:128. PMID:24106473
Dillman A.R., Guillermin M.L., Lee J.H., Kim B., Sternberg P.W., Hallem E.A.. (2012). Olfaction shapes host-parasite interactions in parasitic nematodes. Proc Natl Acad Sci U S A. 2012 Jul 31. [Epub ahead of print] PubMed PMID: 22851767.
Narayan, A., Laurent, G., and Sternberg, P.W. (2011). Transfer characteristics of a thermosensory synapse in Caenorhabditis elegans. Proc Natl Acad Sci U S A. 108:9667-72. PMID: 21606366; PMCID: PMC3111291.
Hallem, E.A., Dillman, A. R., Hong, A. V., Zhang, Y., Yano, J. M., DeMarco, S. F., and Sternberg, P. W. (2011). A sensory code for host seeking in parasitic nematodes. Current Biology 21(5):377-83. PMID: 21353558.
Hallem, E. A., Spencer, W. C., McWhirter, R. D., Zeller, G. Henz, S. R., Rätsch, G. Miller, D. M. III, Horvitz, H. R., Sternberg, P. W., and Ringstad, N. (2010). A receptor-type guanylate cyclase is required for carbon dioxide sensation by C. elegans. Proc Natl Acad Sci U S A. 108(1):254-9. PMID: 2117323. PMCID: PMC3017194
Whittaker, A. J. and Sternberg, P. W. (2009). Coordination of opposing sex-specific and core muscle groups regulates male tail posture during Caenorhabditis elegans male mating behavior. BMC-Biology, Jun 22;7:33.
Van Buskirk, C. and Sternberg, P. W. (2007). EGF signaling induces behavioral quiescence in C. elegans. Nature Neuroscience 10: 1300-1307.
Liu, K. and Sternberg, P. W. (1995). Sensory regulation of male mating behavior in Caenorhabditis elegans. Neuron 14: 79-89.
Chemical Ecology and Ascarosides
Hsueh, Y.-P., Mahanti, P., Schroeder, F. C., and Sternberg, P.W. (2013). Nematode-trapping fungi eavesdrop on nematode pheromones. Curr Biol. 2013 Jan 7;23(1):83-6. doi: 10.1016/j.cub.2012.11.035. Epub 2012 Dec 13. PubMed PMID: 23246407.
Choe, A., von Reuss, S.H., Kogan, D., Gasser, R. B., Platzer, E. G., Schroeder, F. C., and Sternberg, P.W. (2012). Ascaroside signaling is widely conserved among nematodes. Curr Biol. 2012 May 8;22(9):772-80. Epub 2012 Apr 12.PMID:22503501
Izrayelit, Y., Srinivasan, J., Sternberg, P.W., and Schroeder, F. (2012). Targeted metabolomics reveals a male pheromone and sex-specific ascaroside biosynthesis in C. elegans. ACS Chem Biol. 2012 Jun 12. [Epub ahead of print] PubMed PMID: 22662967.
Srinivasan, J., von Reuss, S.H., Bose, N., Zaslaver, A., Mahanti, P., Ho, M.C., O'Doherty, O. Edison, A. S. Sternberg, P.W. and Schroeder, F. C. (2012). A modular library of chemical signals regulates social behaviors in Caenorhabditis elegans. PLoS-Biology 10(1):e1001237. PMID: 22253572.
von Reuss, S., Bose, Neelanjan; Srinivasan, J.; Yim, J.; Sternberg, P.; Schroeder, F. (2012). Comparative metabolomics reveals biogenesis of C. elegans ascarosides, a modular library of small molecule signals. J. Am. Chem. Soc. http://pubs.acs.org/doi/pdf/10.1021/ja210202y
Srinivasan, J., Kaplan, F., Ajredini, R., Zachariah, C., Alborn, H., Teal, P., Malik, R. U., Edison, A. E., Sternberg, P. W., and Schroeder, F. C. (2008). A blend of small molecules regulates both mating and development in Caenorhabditis elegans. Nature 454: 1115-1118.
Artyukhin, A. B., Yim, J. J., Srinivasan, J., Izrayelit, Y., Bose, N., von Reuss, S. H., Jo, Y., Jordan, J. M., Baugh, L. R., Cheong, M., Sternberg, P. W., Avery, L., and Schroeder, F. C. (2013). Succinylated octopamine ascarosides and a new pathway of biogenic amine metabolism in C. elegans. J Biol Chem. 2013 Jun 28;288(26):18778-83. doi: 10.1074/jbc.C113.477000. PMID: 23689506.
Minor, P. J., He, T.-F., Soh, C. H., Asthagiri, A. R., and Sternberg, P. W. (2013). FGF signaling regulates Wnt ligand expression to control vulval cell lineage polarity in C. elegans. Development, Aug 14. [Epub ahead of print] PMID: 23946444
Robinson, C. P. Schwarz, E. M. and Sternberg, P. W. (2013). Identification of DVA interneuron regulatory sequences in Caenorhabditis elegans. PLoS One. 2013;8(1):e54971. doi: 10.1371/journal.pone.0054971. Epub 2013 Jan 28. PMID: 23383017; PMCID: PMC3557239
Dillman, A.R., Minor, P.J., Sternberg, P.W. Origin and evolution of dishevelled. G3 (Bethesda). 2013 Feb;3(2):251-62. doi: 10.1534/g3.112.005314. Epub 2013 Feb 1. PMID: 23390601.
Van Buskirk, C. and Sternberg ,P.W. (2010). Paired and LIM class homeodomain proteins coordinate differentiation of the C. elegans ALA neuron. Development 137(12):2065-2074. PMID: 20501595; PMC2875845.
Yu, H.,Seah, A. and Sternberg, P. W. (2010), Re-programming of C. elegans male epidermal precursor fates by Wnt, Hox, and LIN-12/Notch activities, Dev. Biol. (2010), doi:10.1016/j.ydbio.2010.05.008
Kato M, Sternberg PW. The C. elegans tailless/Tlx homolog nhr-67 regulates astage-specific program of linker cell migration in male gonadogenesis. Development. 2009 Dec;136(23):3907-15. PubMed PMID: 19906858.
Green, J. L., Inoue, T., and Sternberg, P.W. (2008). Opposing Wnt pathways orient cell polarity during organogenesis. Cell 134: 646-656.
Schwarz, E.M., Korhonen, P. K., Campbell, B.E., Young, N. D., Jex, A. R., Jabbar, A., Hall, R. S., Mondal, A., Howe, A.C., Pell, J., Hofmann, A., Boag, P. R., Zhu, X.-Q., Gregory, T. R., Loukasg, A., Williams, B. A., Antoshechkin, I., Brown, C. T., Sternberg, P. W., and Gasser, R. B. (2013). The genome and developmental transcriptome of the strongylid nematode Haemonchus contortus. Genome Biology 2013, 14:R89 doi:10.1186/gb-2013-14-8-r89
Srinivasan, J., Dillman, A. R., Macchietto, M. G., Heikkinen, L., Lakso, M. Fracchia, K. M., Antoshechkin, I., Mortazavi, A., Wong, G., and Sternberg, P.W. (2013) The draft genome and transcriptome of Panagrellus redivivus are shaped by the harsh demands of a free-living lifestyle. Genetics 193:1279-1295. PMID: 23410827; PMCID: PMC3606103.
Bai, X., Adams, B.J., Ciche, T.A., Clifton, S., Gaugler, R., Kim, K.S., Spieth, J., Sternberg, P.W., Wilson, R.K, Grewa,l P.S. (2013). A Lover and a Fighter: The Genome Sequence of an Entomopathogenic Nematode Heterorhabditis bacteriophora. PLoS One. 2013 Jul18;8(7):e69618. doi: 10.1371/journal.pone.0069618. PMID:23874975; PMCID: PMC3715494.
Kuntz, S. G., Williams, B. A., Sternberg, P. W., Wold, B. J. (2012). Transcription factor redundancy and tissue specific regulation: evidence from functional and physical network connectivity. Genome Res. 2012 Jun 22. [Epub ahead of print] PubMed PMID: 22730465
Zaslaver, A., Baugh, L. R. and Sternberg. P. W. (2011). Metazoan operons accelerate recovery from growth arrested states. Cell 145(6):981-92.
Mortazavi, A., Schwarz, E.M., Williams, B., Schaeffer, L., Antoshechkin, I., Wold, B.J., Sternberg, P.W. (2010). Scaffolding a Caenorhabditis nematode genome with RNA-seq. Genome Research 20(12):1740-1747.
Baugh, L. R., DeModena, J. and Sternberg, P. W. (2009). RNA Pol II Accumulates at Promoters of Growth Genes During Developmental Arrest. Science 324(5923):92-94.
Harris, Todd; Baran, Joachim; Bieri, Tamberlyn; Cabunoc, Abigail; Chan, Juancarlos; Chen, Wen; Davis, Paul; Howe, Kevin; Done, James; Grove, Christian; Kishore, Ranjana; Lee, Raymond; Li, Yuling; Müller, Hans-Michael; Nakamura, Cecilia; Ozersky, Philip; Paulini, Michael; Raciti, Daniela; Schindelman, Gary; Tuli, Mary Ann; Van Auken, Kimberly; Wang, Daniel; Wang, Xiaodong; Williams, Gary; Wong, JD; Yook, Karen; Schedl, Tim; Hodgkin, Jonathan; Berriman, Matt; Kersey, Paul; Spieth, John; Stein, Lincoln; Sternberg, Paul. (2014). WormBase 2014: New views of curated biology. Nucleic Acids Res. 2013 Nov 4. [Epub ahead of print] PubMed PMID: 24194605
Fang, R., Schindelman, G., Van Auken, K., Fernandes, J., Chen, W., Wang, X., Davis, P., Tuli, M. A., Marygold, S.J., Millburn, G., Matthews, B., Zhang, H., Brown, N., Gelbart, W. M., and Sternberg, P. W. (2012). Automatic categorization of diverse experimental information in the bioscience literature. BMC Bioinformatics 13(1):16. PMID: 22280404.
Bandrowski, A.E., Cachat, J., Li, Y, Müller, H.M., Sternberg, P.W., Ciccarese, P., Clark, T., Marenco, .L, Wang, R., Astakhov, V., Grethe, J.S., Martone, M.E. (2012). A hybrid human and machine resource curation pipeline for the Neuroscience Information Framework. Database (Oxford). 2012 Mar 20;2012:bas005.
Schindelman, G., Fernandes, J. S., Bastiani, C. A., Yook, K. and Sternberg. P. W. (2011). Worm Phenotype Ontology: Integrating phenotype data within and beyond the C. elegans community. BMC Bioinformatics 12:32.
Rangarajan, A., Schedl, T., Yook, K., Chan, J., Haenel, S., Otis, L., Faelten, S., DePellegrin-Connelly, T., Isaacson, R., Skrzypek, Marygold, S. J., Stefancsik, R., Skrzypek,, M.S. Cherry, J. M., Sternberg, P. W., and Müller, H.-M. (2011). Toward an interactive article: integrating journals and biological databases. BMC Bioinformatics 12:175
Van Auken, K., Jaffery, J., Chan, J. N., Müller H.-M., and Sternberg, P. W. (2009). Semi-automated curation of protein subcellular localization: a text mining-based approach to Gene Ontology (GO) cellular component curation. BMC Bioinformatics 10:228 doi:10.1186/1471-2105-10-228.
Mueller, H.-M., Kenny, E., and Sternberg, P. W. (2004). Textpresso: an ontology-based information retrieval and extraction system for C. elegans literature. PLoS Biol 2(10): e309.
Evolution of Behavior or Development
Rivard L, Srinivasan J, Stone A, Ochoa S, Sternberg PW, Loer CM. A comparison of experience-dependent locomotory behaviors and biogenic amine neurons in nematode relatives of Caenorhabditis elegans. BMC Neurosci. 2010 Feb 19;11:22.
Srinivasan J, Durak O, Sternberg PW. Evolution of a polymodal sensory response network. BMC Biol. 2008 Dec 15;6:52.
Sommer, R. J. and Sternberg, P. W. (1994). Changes of induction and competence during the evolution of vulva development in nematodes. Science 265: 114-118.
Ansell, B.R., Schnyder, M., Deplazes, P., Korhonen, P.K., Young, N.D., Hall, R.S., Mangiola, S, Boag, P.R., Hofmann, A., Sternberg, P.W., Jex, A.R., Gasser, R.B. Insights into the immuno-molecular biology of Angiostrongylus vasorum through transcriptomics –prospects for new interventions. Biotechnol Adv. 2013 Jul 26. doi:pii:S0734-9750(13)00120-1. 10.1016/j.biotechadv.2013.07.006. [Epub ahead of print] PMID: 23895945.
Dillman, A. R. and Sternberg. P. W. (2012). Quick guide: entomopathogenic nematodes. Curr Biol. 2012 Jun 5;22(11):R430-1.
Dillman, A. R., Chaston, J. M., Adams, B. J., Ciche, T. A., Goodrich-Blair, H., Stock, S. P., and Sternberg, P. W. (2012). An entomopathogenic nematode by any other name. PLoS-Pathogens, in press.
Jex, A. R., Li, B., Young, N. D., Hall, R. S., Yang, L., Liu, S., Xun, X., Xiong, Z., Chen, F., Wu, X., Zhou, G., Fan, X., Campbell, B. E., Cantacessi, C. Schwarz, E. M. Ranganathan, S., Geldhof, P., Nejsum, P., Sternberg, P. W., Wang, J. Yang, H. and Gasser, R. B. (2011). The Ascaris suum genome. Nature 479(7374):529-533.
Campbell, B. E. Boag, P.R., Hofmann, A., Cantacessi, C., Wang, C. K., Taylor, P., Hu, M., Sindhu, Z., Loukas, A., Sternberg, P.W., and Gasser, R.B. (2011). Atypical (RIO) protein kinases from Haemonchus contortus - Promise as new targets for nematocidal drugs. Biotechnol Adv. 2011 May-Jun;29(3):338-50.
Cantacessi C, Jex AR, Hall RS, Young ND, Campbell BE, Joachim A, Nolan MJ, Abubucker S, Sternberg PW, Ranganathan S, Mitreva M and Gasser RB (2010) A practical, bioinformatic workflow system for large datasets generated by next generation sequencing. Nucleic Acids Research 38, e171.
Cantacessi C, Mitreva M, Jex AR, Young ND, Campbell BE, Hall RS, Doyle MA, Ralph SA, Rabelo EM, Ranganathan S, Sternberg PW, Loukas A, Gasser RB. Massively parallel sequencing and analysis of the Necator americanus transcriptome. PLoS Negl Trop Dis. 2010 May 11;4(5):e684.
BioEngineering and Modeling
Chiu, H., Schwartz, H. T., Antoshechkin, I., and Sternberg, P. W. (2013). Transgene-free genome editing in Caenorhabditis elegans using CRISPR-Cas. Genetics, in press. Early online August 26, 2013, doi:10.1534/genetics.113.155879
Choe A., Chuman T., von Reuss S.H., Dossey A.T., Yim J.J,. Ajredini .R, Kolawa A.A., Kaplan F., Alborn H.T., Teal P.E., Schroeder F.C., Sternberg P.W., Edison A.S. Sex-specific mating pheromones in the nematode Panagrellus redivivus. Proc Natl Acad Sci U S A. 2012 Dec 18;109(51):20949-54. doi: 10.1073/pnas.1218302109. Epub 2012 Dec 3. PubMed PMID: 23213209; PubMed Central PMCID: PMC3529029.
Chung, K., Zhan, M., Srinivasan, J., Sternberg, P. W., Gong, E., Schroeder, F., and Lu, H. (2011). Microfluidic chamber arrays for whole-organism high-throughput chemical screening. Lab Chip. 2011 Nov 7;11(21):3689-97. Epub 2011 Sep 20. PubMed PMID: 21935539.
Pang, S., Cui, X., DeModena, J., Wang, Y.M., Sternberg, P., Yang, C. Implementation of a color-capable optofluidic microscope on a RGB CMOS color sensor chip substrate. Lab Chip 10(4):411-4. Epub 2010 Jan 5. PMID: 20126679.
Giurumescu, C. A., Sternberg, P. W. and Asthagiri, A. R. (2009). Predicting phenotypic diversity and the underlying quantitative molecular transitions. PLoS Comput. Biol. 5(4): e1000354.
Cui, X., Lee, L. M., Heng, X., Zhong, Z., Sternberg, P. W., Psaltis, D., and Yang, C. (2008). Imaging microorganisms with a high resolution on-chip optofluidic microscope. Proc. Natl. Acad. Sci., USA, 105(31):10670-10675.
Cronin, C. J., Mendel, J. E., Muhktar, S., Kim, Y.-M., Stirbl, R. C., Bruck, J., and Sternberg, P. W. (2005). An automated system for measuring parameters of nematode sinusoidal movement. BMC-Genetics 6: 5 (7 Feb2005).
Levchenko, A., Bruck, J., and Sternberg, P. W. (2000). Scaffold proteins may biphasically affect the levels of MAP kinase signaling and reduce its threshold properties. Proc. Natl. Acad. Sci. USA 97(11): 5818-5823.