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Pathway cross-talk

The aim of this project is to find molecules (proteins or chemicals) that are not yet curated in Reactome that can bridge two existing pathways.

This approach should help curators to identify low-hanging fruit molecules to enter in Reactome and also create meaningful connections between different domains of biology that are not yet annotated in our database.

Strategy:

The first step to identify a target interactor that bridges two pathways is to find a molecule that interacts with two existing reference entities (A and B). An initial requirement for the script is that this interacting molecule does not have to be curated in Reactome. For this step, we use data integrated from the IntAct database and stored directly in the UndirectedInteraction class instances in our graph database.

Let's start sketching the described interaction between two existing reference entities (A and B) and the target interactor bridge (which is the new molecule to be curated in Reactome) like:

                          ___score___    ___score___           
                         |     A     |  |     B     |          
                         |           |  |           |          
                      reference - interactor - reference    
                       entity       bridge      entity         
                         A          ^^^^^^        B

Based on IntAct data, each interaction has a score assigned. The score for the interaction between the reference entity A and the interactor bridge is score A. The same principle applies for the interaction between the interactor bridge and reference entity B (score B).

Extending the sketch presented above, the next step is to include physical entities. Physical entity A and Physical entity B point to reference entity A and reference entity B respectively. The caveat here is that both physical entities must share compartment and must not have modified residues.

               _______/     SHARE COMPARTMENT AND     \_______
              |       \ DO NOT HAVE MODIFIED RESIDUES /       |
              |                                               |
              |           ___score___    ___score___          |
              |          |     A     |  |     B     |         |
              |          |           |  |           |         |
           physical > reference - interactor - reference < physical
            entity     entity       bridge      entity      entity
              A          A          ^^^^^^        B           B

It is also important to note that to ensure that the interaction can take place as defined in IntAct, the corresponding physical entities do not have to be part of complexes or entity sets for the time being.

               _______/     SHARE COMPARTMENT AND     \_______
              |       \ DO NOT HAVE MODIFIED RESIDUES /       |
              |                                               |
              |           ___score___    ___score___          |
              |          |     A     |  |     B     |         |
              |          |           |  |           |         |
           physical > reference - interactor - reference < physical
            entity     entity       bridge      entity      entity
              A          A          ^^^^^^        B           B
              |                                               |
              |_____________ DIRECTLY IN DIAGRAM _____________|

Finally, it is time to include the pathways for which the interactor bridge will be reported. Being pathway A the one where physical entity A is present and pathway B for physical entity B.

     ________________________ NOT NESTED EVENTS _________________________        
    |                                                                    |      
    |          _______/     SHARE COMPARTMENT AND     \_______           |      
    |         |       \ DO NOT HAVE MODIFIED RESIDUES /       |          |      
    |         |                                               |          |      
    |         |           ___score___    ___score___          |          |      
    |         |          |     A     |  |     B     |         |          |      
    |         |          |           |  |           |         |          |      
 pathway > physical > reference - interactor - reference < physical < pathway   
    A       entity     entity       bridge      entity      entity       B      
    |         A          A          ^^^^^^        B           B          |      
    |         |                                               |          |      
    |         |_____________ DIRECTLY IN DIAGRAM _____________|          |      
    |                                                                    |      
    |___________________________ SAME SPECIES ___________________________|

It is important to mention two main points:

  1. Both pathways have to belong to the same species (although for the time being only 'Homo sapiens' pathways are reported)
  2. These pathways must not be nested.

Result report explained:

For this explanation, we use the result of executing the script against data for release 67 using a threshold score of 0.75. Every pair of bridgeable pathways are reported as follow (in a csv file):

Report entry          
R-HSA-193704 p75 NTR receptor-mediated signalling          
R-HSA-5633008 TP53 Regulates Transcription of Cell Death Genes          
Score: 0.90602           Common physical entities: 0
    UniProt:Q07817-1 BCL2L1        
      UniProt:O43521 BCL2L11 <-[0.935]- UniProt:Q07817-1 BCL2L1 -[0.969]-> UniProt:Q07812 BAX Score: 0.90602
      BCL2L11 [cytosol]   BAX [cytosol]  
      UniProt:O43521 BCL2L11 <-[0.935]- UniProt:Q07817-1 BCL2L1 -[0.862]-> UniProt:P55957 BID Score: 0.80597
      BCL2L11 [cytosol]   BID(1-195) [cytosol]  
      UniProt:O43521 BCL2L11 <-[0.935]- UniProt:Q07817-1 BCL2L1 -[0.855]-> UniProt:Q9BXH1 BBC3 Score: 0.79943
      BCL2L11 [cytosol]   BBC3 [cytosol]  
      UniProt:Q92934 BAD <-[0.807]- UniProt:Q07817-1 BCL2L1 -[0.969]-> UniProt:Q07812 BAX Score: 0.78198
      BAD [cytosol]   BAX [cytosol]  
      UniProt:Q92934 BAD <-[0.807]- UniProt:Q07817-1 BCL2L1 -[0.862]-> UniProt:P55957 BID Score: 0.69563
      BAD [cytosol]   BID(1-195) [cytosol]  
      UniProt:Q92934 BAD <-[0.807]- UniProt:Q07817-1 BCL2L1 -[0.855]-> UniProt:Q9BXH1 BBC3 Score: 0.68999
      BAD [cytosol]   BBC3 [cytosol]  
    UniProt:Q92843 B2CL2        
      UniProt:O43521 BCL2L11 <-[0.855]- UniProt:Q92843 B2CL2 -[0.750]-> UniProt:P55957 BID Score: 0.64125
      BCL2L11 [cytosol]   BID(1-195) [cytosol]  

The first two lines show pathway A and pathway B (identifier and name). The third line shows (1) the highest combined score amongst the different interactions found for each interactor bridge and their interacting molecules in each pathway, (2) the common physical entities already existing between pathway A and pathway B and (3) when there are common physical entities between pathway A and pathway B, those are also enumerated.

The following lines for an entry report the molecule acting as the interactor bridge (e.g. "UniProt:Q07817-1 BCL2L1") followed with all the found interactions between it and participating molecules in pathway A and pathway B. Let's use one of them as example:

UniProt:O43521 BCL2L11 <-[0.935]- UniProt:Q07817-1 BCL2L1 -[0.969]-> UniProt:Q07812 BAX
BCL2L11 [cytosol]                                                    BAX [cytosol]

The above says that "UniProt:O43521 BCL2L11" is present in pathway A and it interacts with the interactor bridge with a score of 0.935. At the same time, the interactor bridge interacts with "UniProt:Q07812 BAX" (present in pathway B) with a score of 0.969. The combined score for this interaction is shown in the next column. It is calculated by multiplying both score A and score B.

BCL2L11 [cytosol] and BAX [cytosol] are clickable so it is easier to see the target existing molecules directly in the pathways that are target for cross-talk in this entry.

Usage:

This project can be used as a standalone compiled tool:

java -jar interactor-bridge-jar-with-dependencies.jar --help

Usage:
  Main [--help] [(-h|--host) <host>]
  [(-p|--port) <port>] [(-u|--user) <user>] [(-s|--score) <score>] (-o|--output)
  <output> (-k|--password) <password>

Reports interactors as possible bridges between pathways in Reactome

  [--help]
        Prints this help message.

  [(-h|--host) <host>]
        The neo4j host (default: localhost)

  [(-p|--port) <port>]
        The neo4j port (default: 7474)

  [(-u|--user) <user>]
        The neo4j user (default: neo4j)

  [(-s|--score) <score>]
        Threshold score for IntAct interactions (range [0.45, 1]) (default: 0.45)

  (-o|--output) <output>
        Output file

  (-k|--password) <password>
        The neo4j password (default: neo4j)