the ucsd - nature signaling gateway ( http://www.signaling-gateway.org ) is a collaboration between the university of california , san diego and the nature publishing group ( npg ) , designed to facilitate navigation of the complex world of research into cellular signaling .
the signaling gateway is made up of three components : the molecule pages ( described in this study ) , the signaling update and the data center .
the signaling update is published weekly by the npg to provide topical and timely information about progress in signal transduction research .
the signaling gateway was formerly sponsored by the alliance for cellular signaling ( afcs ) ( 1,2 ) , which performed comprehensive experimental analyses of selected signaling systems .
the data center section of the web site contains all the data generated by the afcs during the period signaling gateway was part of the afcs .
the signaling gateway molecule pages ( sgmp ) database provides essential information on more than 3800 proteins involved in cellular signaling in mammals , with each protein having its own molecule page .
molecule page information is presented in two categories : author - entered data and automated data .
author - entered data contain expert - authored and peer - reviewed information based on published literature , with both review style free text with citations , and highly structured data for bioinformatic interrogation .
the information is linked to appropriate journal citations , and covers areas such as protein interactions and states , transitions between states and protein function .
the automated data information is a collection of public bioinformatic data source links and sequence analysis results , derived from the sequence and data record used to define the molecule page .
the sgmp base organism is mus musculus ( because of the mouse - centric focus of the afcs ) , though much of the information in the sgmp is derived from homologous proteins in other species , such as homo sapiens .
once the author - entered information has gone through a peer review process , the molecule page is published .
the published molecule pages are citable and to date npg has published entries for 365 proteins , with nearly 130 submitted molecule pages currently in the review system , and 350 molecule pages in author preparation .
new published molecule pages are promoted through the signaling update website pages , e - alerts and linkouts from npg content .
the sgmp is a complicated online annotation and publishing system , containing three major subcomponents : ( i ) online pathway curation ( author - entered data ) ; ( ii ) online peer review and ( iii ) public repository data acquisition and display ( automated data ) . the peer review information and the pre - published author - entered information for a given molecule page are only visible to the author , selected reviewers and the editorial staff , and are invisible to all other users .
each molecule page is assigned a specific protein sequence , a name , a list of synonyms and a specific protein function category ( based on 
that information is used to generate the properties of the sequence such as molecular weight , and all the automated data associated with the sequence . a combination of database links and computational methods are used to find the related database records and the parameters of computational matches ( e.g. a domain region ) .
this information is displayed in the  protein overview section of the molecule page , which is the landing page for unpublished molecule pages . to illustrate the depth of the author - entered data , we choose adenylyl cyclase type 5 ( sgmp i d a000001 ) . because this is a published molecule page
, the user first arrives at the  abstract section , which gives information on the author ( carmen w. dessauer ) , gives a summary of the role of adenylyl cyclase type 5 , lists the names and synonyms provided by the author and the editors , indicates that a000001 molecule has 32 enzyme functions , exists in 33 states , has 96 transitions between these states , and shows a miniature version of the network map of these transitions .
the  full text section contains a textual description  with published references  of protein function , regulation , interactions , subcellular localization , expression , phenotypes , splice variants and antibodies .
the  states section lists each defined functional state , with links to a constituent list and a transition graph ( if applicable ) to indicate all the transitions that lead to the state .
a protein state is defined by the principal proteins interactions with other protein partners , covalent modifications on all protein components , association with small molecule ligands and cellular location .
transitions section shows a list of the defined transitions , with a link to detailed information on each transition  with initial and final state information , the change that occurred in the transition , process information , other comments and citations ( figure 1 ) .
a transition is defined as a biological process that causes the conversion of a protein from one state to another .
network map gives a graphical representation of all the states , and the transitions between them , defined by the author for a000001 ( figure 2 ) .
functions section shows that a000001 acts as an enzyme , catalyzing the conversion of mg - atp to cyclic amp and pyrophosphate .
each state that catalyzes the reaction is listed , with a link to the detailed state information , and a link to detailed function information with reaction information , comments and citations ( figure 3 ) .
the  protein classes section shows classes defined by the author to aid in data entry and display  a class is defined as a group of three or more proteins that behave identically in a particular state . 

the  protein records section displays all the sequence database records related to particular molecule page .
a specific record , defined by an ncbi protein gi number ( 3 ) , is assigned to the molecule page as a base sequence .
all the other sequence records listed in the same entrez gene ( 4 ) record are displayed , as well as any uniprot ( 5 ) and ensembl ( 6 ) records that refer to those sequence records .
the  gene info page displays pertinent information related to the molecule from the entrez gene record , including any related ensembl gene records or the sequence records within it .
the  domains & motifs ( figure 4 ) section contains domain information pfam ( 7 ) and smart ( 8) , pattern / motif information from prints ( 9 ) and interpro ( 10 ) records related to the molecule page sequence . these records are produced using a combination of database record references , computational schemes [ hmmpfam ( 11 ) and fingerprintscan ( 12 ) ] . matching sequence regions are given for the computational matches .
the  interactions page displays matching interaction database records from the bind database and from the entrez gene database , including bind ( 13 ) , biogrid ( 14 ) and hprd ( 15 ) interaction records .
interactions involving likely orthologs of the molecule page base sequence are displayed , to provide additional information .
orthologs section shows genes in other select organisms that are likely orthologs of the base gene .
this list is constructed using a combination of a species - specific blast against the ncbi protein database , and database analysis of homologene ( 16 ) and ensembl homology databases .
blast data section contains a list of the top blast hits against the entire ncbi protein database . the protein 
structure section displays the pdb ( 17 ) records that are related to the molecule page , either through a database reference to one of the related protein sequence records , or by a sequence match with blast . 

in addition to all the hyperlinks to the relevant bioinformatic databases , the sgmp base sequence also links directly to the sdsc biology workbench ( http://workbench.sdsc.edu ) .
the biology workbench ( 18 ) enables a user to carry out seamlessly a variety of sequence analysis operations .
to illustrate the depth of the author - entered data , we choose adenylyl cyclase type 5 ( sgmp i d a000001 ) . because this is a published molecule page ,
the user first arrives at the  abstract section , which gives information on the author ( carmen w. dessauer ) , gives a summary of the role of adenylyl cyclase type 5 , lists the names and synonyms provided by the author and the editors , indicates that a000001 molecule has 32 enzyme functions , exists in 33 states , has 96 transitions between these states , and shows a miniature version of the network map of these transitions .
the  full text section contains a textual description  with published references  of protein function , regulation , interactions , subcellular localization , expression , phenotypes , splice variants and antibodies .
states section lists each defined functional state , with links to a constituent list and a transition graph ( if applicable ) to indicate all the transitions that lead to the state .
a protein state is defined by the principal proteins interactions with other protein partners , covalent modifications on all protein components , association with small molecule ligands and cellular location .
transitions section shows a list of the defined transitions , with a link to detailed information on each transition  with initial and final state information , the change that occurred in the transition , process information , other comments and citations ( figure 1 ) .
a transition is defined as a biological process that causes the conversion of a protein from one state to another .
network map gives a graphical representation of all the states , and the transitions between them , defined by the author for a000001 ( figure 2 ) .
functions section shows that a000001 acts as an enzyme , catalyzing the conversion of mg - atp to cyclic amp and pyrophosphate .
each state that catalyzes the reaction is listed , with a link to the detailed state information , and a link to detailed function information with reaction information , comments and citations ( figure 3 ) .
the  protein classes section shows classes defined by the author to aid in data entry and display  a class is defined as a group of three or more proteins that behave identically in a particular state . 

the  protein records section displays all the sequence database records related to particular molecule page . a specific record , defined by an ncbi protein gi number ( 3 ) ,
all the other sequence records listed in the same entrez gene ( 4 ) record are displayed , as well as any uniprot ( 5 ) and ensembl ( 6 ) records that refer to those sequence records .
the  gene info page displays pertinent information related to the molecule from the entrez gene record , including any related ensembl gene records or the sequence records within it .
the  domains & motifs ( figure 4 ) section contains domain information pfam ( 7 ) and smart ( 8) , pattern / motif information from prints ( 9 ) and interpro ( 10 ) records related to the molecule page sequence .
these records are produced using a combination of database record references , computational schemes [ hmmpfam ( 11 ) and fingerprintscan ( 12 ) ] . matching sequence regions
the  interactions page displays matching interaction database records from the bind database and from the entrez gene database , including bind ( 13 ) , biogrid ( 14 ) and hprd ( 15 ) interaction records .
interactions involving likely orthologs of the molecule page base sequence are displayed , to provide additional information .
orthologs section shows genes in other select organisms that are likely orthologs of the base gene .
this list is constructed using a combination of a species - specific blast against the ncbi protein database , and database analysis of homologene ( 16 ) and ensembl homology databases .
the  blast data section contains a list of the top blast hits against the entire ncbi protein database .
structure section displays the pdb ( 17 ) records that are related to the molecule page , either through a database reference to one of the related protein sequence records , or by a sequence match with blast . 

in addition to all the hyperlinks to the relevant bioinformatic databases , the sgmp base sequence also links directly to the sdsc biology workbench ( http://workbench.sdsc.edu ) . the biology workbench ( 18 ) enables a user to carry out seamlessly a variety of sequence analysis operations .
the advisory board provides high - level guidance and advice concerning the development of the molecule pages database .
the editorial board helps the editorial team with several aspects of publishing molecule pages , such as identifying relevant authors , reviewers and adjudication during peer - review .
npg manages a rigorous editorial process to ensure that expert - authored molecule pages are accurate and complete , and that structured data is recorded in a consistent manner .
authors either apply to contribute and are selected by npg editors , or are commissioned by editors . after an initial editorial evaluation of an author 's submission ,
the molecule page undergoes anonymous peer - review by two or three experts in the relevant field . following peer - review
the author may be required to revise their submission in light of reviewer and editor comments .
following revision the molecule page is critically assessed and a decision to publish is made .
the molecule page is copy edited before publication and a digital object identifier ( doi ) assigned upon publication .
the database tier is an oracle 10 g database instance running on a sun server .
the middle tier contains business and web components and is deployed on an oracle components 4 java ( oc4j ) application server that also runs on a sun server .
the business components consist of data access objects that encapsulate database access for the web layer .
the web layer consists of java servlets and server pages complying with the j2ee ( enterprise java ) 1.3 specifications .
the compute and database servers are located at the san diego supercomputer center ( sdsc ) .
in addition to the web forms that the general public uses for viewing the data , there are specialized web forms for the authors , reviewers and editors to perform their tasks . a password - protected user access system controls access to the specialized forms and the unpublished data for a given molecule page , but
the general public is able to access any published data and all automated data without having to register for an account .
local copies of the constituent databases are stored in custom , relational forms on the oracle system , with the computational methods being run on sun systems .
the results of the automated data are stored in the database tier , along with the archived results of automated analysis at the time of publication .
tab - delimited files relating the molecule pages to protein sequence database records ( e.g. uniprot , refseq , genbank ) and gene database records ( entrez gene and ensembl ) are provided via anonymous ftp .
the data is accessed via a browse function , a simple search engine and an advanced search engine .
the simple search engine allows users to query the database using the molecule page i d , gene symbols , protein names and synonyms .
the advanced search engine allows users to ask complex questions , such as  show me all functional states involving molecule a and molecule b. the advanced search engine uses the lucene library ( http://lucene.apache.org/ ) from the apache software foundation ( http://www.apache.org/)an open - source java toolset .
a wiki will be added to the web site , allowing for open comments on any given molecule page , as well as a living molecule summary that does not require the rigorous process of a published molecule page .
previously published molecule pages will be updated by the authors , and released as subsequent versions .
we plan on adding exportable molecule page information , for published molecule pages , in xml form , as well as standard exchange formats such as biopax ( http://www.biopax.org/ ) .
we will continue to add to the links provided in the automated data sections , addressing areas such as gene expression and phosphorylation .
 the ucsd - nature signaling gateway molecule pages ( http://www.signaling-gateway.org/molecule ) provides essential information on more than 3800 mammalian proteins involved in cellular signaling . 
 the molecule pages contain expert - authored and peer - reviewed information based on the published literature , complemented by regularly updated information derived from public data source references and sequence analysis . 
 the expert - authored data includes both a full - text review about the molecule , with citations , and highly structured data for bioinformatics interrogation , including information on protein interactions and states , transitions between states and protein function . 
 the expert - authored pages are anonymously peer reviewed by the nature publishing group . 
 the molecule pages data is present in an object - relational database format and is freely accessible to the authors , the reviewers and the public from a web browser that serves as a presentation layer . 
 the molecule pages are supported by several applications that along with the database and the interfaces form a multi - tier architecture . 
 the molecule pages and the signaling gateway are routinely accessed by a very large research community . 
INTRODUCTION
DATABASE CONTENT
Author-entered data
Automated data
EDITORIAL PROCESS
DATABASE IMPLEMENTATION
FUTURE DIRECTIONS