#acl All:read

= Cell-Cell Interaction Database =
<<TableOfContents(5)>>

DOI: [[https://doi.org/10.5281/zenodo.7589953|10.5281/zenodo.7589953]]
== Overview ==

This page describes the automated construction of a cell-cell interaction database by filtering existing curated protein-protein interaction (PPI) data. Cell-cell interactions are important for understanding tissue organization. We and others have built cell-cell interaction databases ([[#ref1|1]],[[#ref2|2]],[[#ref3|3]],[[#ref4|4]],[[#ref5|5]]).  The resource available from this website represents an automatically built set of protein-protein interactions that can mediate cell-cell communication that is expanded compared to previous databases we have built.

{{attachment:ligand_receptor_flowchart_ppionly.png|Network creation flowchart|width=750}}

== Defining Receptor and Ligands ==
=== Receptors ===
'''Receptor genes were defined based on the union of the annotations from''' 
  1.  the set of [[http://www.geneontology.org/|Gene Ontology]] (GO) terms([[#ref6|6]],[[#ref7|7]]): 
    * GO:0043235 - receptor complex, 
    * GO:0008305 - integrin complex, 
    * GO:0072657 - protein localized to membrane 
    * GO:0043113 - receptor clustering
    * GO:0004872 - receptor activity,
    * GO:0009897 - external side of plasma membrane)
  1. [[https://www.uniprot.org/|UniProt]] annotations
    * search term -"Receptor [KW-0675]" go:0005886 organism:human. 

'''This created a set of 4364 receptor genes (prior to manual curation)'''

=== Ligands ===
'''Ligand genes were defined based on the union of the below annotations''' 
  1. the GO terms([[#ref6|6]],[[#ref7|7]]):
    *  GO:0005102 - receptor binding 
  1. the set of proteins labelled as secreted in the Secretome dataset (http://www.proteinatlas.org/humanproteome/secretome) ([[#ref8|8]]).  

'''This created a set of 3209 Ligand genes (prior to manual curation)'''

=== Extracellular Matrix ===

'''Extracellular Matrix (ECM) genes were defined based on the union of the annotations from'''
  1. the GO terms([[#ref6|6]],[[#ref7|7]]):
    * GO:0031012 - extracellular matrix
    * GO:0005578 - proteinacious extracellular matrix
    * GO:0005201 - extracellular matrix structural constituent
    * GO:1990430 - extracellular matrix protein binding 
    * GO:0035426 - extracellular matrix cell signalling

'''This created a set of 433 ECM genes (prior to manual curation)'''

=== Manual Curation ===
'''ECM, Receptor and ligand lists were manually curated''' 
  * genes that were neither receptors or ligands were removed
  * misclassified genes were moved to the correct list (i.e. receptors found on the ligand list or vice versa)

After curation, the resulting ligand, receptor and ECM sets consisted of:
  * Receptors - 1851 genes
  * Ligands - 1593 genes
  * ECM - 433 genes
In each of the above sets there are genes that are part of other sets (e.g. a gene can be ECM and ligand at the same time)

== Interaction Data ==

The set of protein interactions were downloaded from:
  1. [[http://irefindex.org/wiki/index.php?title=iRefIndex| iRefIndex]] ([[http://irefindex.org/download/irefindex/data/archive/release_14.0/|version 14]]) ([[#ref9|9]]).  - all BioGRID interactions were excluded from the iRefIndex set as we imported the original source. 
  1. [[http://www.pathwaycommons.org/|Pathway Commons]] ([[http://www.pathwaycommons.org/archives/PC2/v8/|version 8]])([[#ref10|10]]).
  1. [[https://thebiogrid.org/|BioGRID]] ([[https://downloads.thebiogrid.org/BioGRID/Release-Archive/BIOGRID-3.4.147/|version 3.4.147]])([[#ref11|11]]).

The entire interaction set was filtered to only include interactions that contained receptor-ligand, receptor-receptor, ligand-ligand, receptor-ecm, ligand-ecm or ecm-ecm interactions where the receptor, ligands and ecm were defined by the above lists. 

'''The resulting Receptor-Ligand network contained 2,593 unique proteins and 38,446 unique interactions (115,900 interaction total)'''

== Download Data ==
=== Molecule Definition files ===
 1. [[attachment:ligands.txt|Ligands]] - table of ligands. (contains HGNC symbol and classification (Ligand, Ligand/ECM, Ligand/Receptor, Ligand/ECM/Receptor)  
 1. [[attachment:receptors.txt|Receptors]] - table of receptors. (contains HGNC symbol and classification (Receptor, Receptor/ECM, Ligand/Receptor, Ligand/ECM/Receptor) 
 1. [[attachment:ecm.txt|ECM]] - table of ECM. (contains HGNC symbol and classification (ECM, ECM/Receptor, ECM/Ligand, Ligand/ECM/Receptor) 
 1. [[attachment:protein_types.txt|Protein types]] - table of unique set of receptor, ligand and ECM genes (contains HGNC symbol as well as classification (Receptor, Ligand, ECM, ECM/Receptor, ECM/Ligand, Receptor/Ligand, Ligand/ECM/Receptor) 

=== Interaction files ===
'''Version 1.0''' - Built April 25, 2017 and contains iRefIndex version 14, Pathway Commons version 8 and BioGRID version 3.4.147
 1. [[attachment:receptor_ligand_interactions_mitab_v1.0_April2017.txt.zip|Ligand - Receptor interaction set]] - tab delimited file in [[https://psicquic.github.io/MITAB25Format.html|mitab 2.5]] format containing the following columns: (For people having issues unzipping the file on windows try - [[attachment:receptor_ligand_interactions_mitab_v1.0_April2017.txt.gz| alternate file compatible with windows]] ) 
    * '''AliasA''' - main Alias for molecule A (often the recognized gene symbol)
    * '''AliasB'''- main Alias for molecule B (often the recognized gene symbol)
    * '''uidA'''  - unique identifier for molecule A (depending on the source database this can be one of the following types uniprot, refseq, entrez gene id, ensembl)
    * '''uidB''' - unique identifier for molecule A (depending on the source database this can be one of the following types uniprot, refseq, entrez gene id, ensembl)
    * '''altA''' - list of alternate identifiers for molecule A.
    * '''altB''' - list of alternate identifiers for molecule B.
    * '''aliasA''' - list of alternate aliases for molecule A.
    * '''aliasB''' - list of alternate aliases for molecule B.
    * '''method''' - list of psi-mi terms indicating experimental methods used to discover interaction.
    * '''author''' - text listing authors
    * '''pmids''' - list of pmids associated with the interaction.
    * '''taxa''' - taxon id for molecule A.
    * '''taxb''' - taxon id for molecule B.
    * '''interactionType''' - list of psi-mi terms indicating the type of interactions it is.
    * '''sourcedb''' - source database.
    * '''interactionIdentifier''' - source database interaction identifier
    * '''confidence''' - confidence of interaction as supplied by database source


== References ==
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