Community detection in empirical kinase networks identifies new potential members of signalling pathways.
Phosphoproteomics allows one to measure the activity of kinases that drive the fluxes of signal transduction pathways involved in biological processes such as immune function, senescence and cell growth. However, deriving knowledge of signalling network circuitry from these data is challenging due t...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2023-06-01
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| Series: | PLoS Computational Biology |
| Online Access: | https://doi.org/10.1371/journal.pcbi.1010459 |
| _version_ | 1827348636741140480 |
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| author | Celia De Los Angeles Colomina Basanta Marya Bazzi Maruan Hijazi Conrad Bessant Pedro R Cutillas |
| author_facet | Celia De Los Angeles Colomina Basanta Marya Bazzi Maruan Hijazi Conrad Bessant Pedro R Cutillas |
| author_sort | Celia De Los Angeles Colomina Basanta |
| collection | DOAJ |
| description | Phosphoproteomics allows one to measure the activity of kinases that drive the fluxes of signal transduction pathways involved in biological processes such as immune function, senescence and cell growth. However, deriving knowledge of signalling network circuitry from these data is challenging due to a scarcity of phosphorylation sites that define kinase-kinase relationships. To address this issue, we previously identified around 6,000 phosphorylation sites as markers of kinase-kinase relationships (that may be conceptualised as network edges), from which empirical cell-model-specific weighted kinase networks may be reconstructed. Here, we assess whether the application of community detection algorithms to such networks can identify new components linked to canonical signalling pathways. Phosphoproteomics data from acute myeloid leukaemia (AML) cells treated separately with PI3K, AKT, MEK and ERK inhibitors were used to reconstruct individual kinase networks. We used modularity maximisation to detect communities in each network, and selected the community containing the main target of the inhibitor used to treat cells. These analyses returned communities that contained known canonical signalling components. Interestingly, in addition to canonical PI3K/AKT/mTOR members, the community assignments returned TTK (also known as MPS1) as a likely component of PI3K/AKT/mTOR signalling. We drew similar insights from an external phosphoproteomics dataset from breast cancer cells treated with rapamycin and oestrogen. We confirmed this observation with wet-lab laboratory experiments showing that TTK phosphorylation was decreased in AML cells treated with AKT and MTOR inhibitors. This study illustrates the application of community detection algorithms to the analysis of empirical kinase networks to uncover new members linked to canonical signalling pathways. |
| first_indexed | 2024-03-08T00:15:07Z |
| format | Article |
| id | doaj.art-6ea4b07a280243fe9d1d668fc29d361f |
| institution | Directory Open Access Journal |
| issn | 1553-734X 1553-7358 |
| language | English |
| last_indexed | 2024-03-08T00:15:07Z |
| publishDate | 2023-06-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Computational Biology |
| spelling | doaj.art-6ea4b07a280243fe9d1d668fc29d361f2024-02-17T05:31:19ZengPublic Library of Science (PLoS)PLoS Computational Biology1553-734X1553-73582023-06-01196e101045910.1371/journal.pcbi.1010459Community detection in empirical kinase networks identifies new potential members of signalling pathways.Celia De Los Angeles Colomina BasantaMarya BazziMaruan HijaziConrad BessantPedro R CutillasPhosphoproteomics allows one to measure the activity of kinases that drive the fluxes of signal transduction pathways involved in biological processes such as immune function, senescence and cell growth. However, deriving knowledge of signalling network circuitry from these data is challenging due to a scarcity of phosphorylation sites that define kinase-kinase relationships. To address this issue, we previously identified around 6,000 phosphorylation sites as markers of kinase-kinase relationships (that may be conceptualised as network edges), from which empirical cell-model-specific weighted kinase networks may be reconstructed. Here, we assess whether the application of community detection algorithms to such networks can identify new components linked to canonical signalling pathways. Phosphoproteomics data from acute myeloid leukaemia (AML) cells treated separately with PI3K, AKT, MEK and ERK inhibitors were used to reconstruct individual kinase networks. We used modularity maximisation to detect communities in each network, and selected the community containing the main target of the inhibitor used to treat cells. These analyses returned communities that contained known canonical signalling components. Interestingly, in addition to canonical PI3K/AKT/mTOR members, the community assignments returned TTK (also known as MPS1) as a likely component of PI3K/AKT/mTOR signalling. We drew similar insights from an external phosphoproteomics dataset from breast cancer cells treated with rapamycin and oestrogen. We confirmed this observation with wet-lab laboratory experiments showing that TTK phosphorylation was decreased in AML cells treated with AKT and MTOR inhibitors. This study illustrates the application of community detection algorithms to the analysis of empirical kinase networks to uncover new members linked to canonical signalling pathways.https://doi.org/10.1371/journal.pcbi.1010459 |
| spellingShingle | Celia De Los Angeles Colomina Basanta Marya Bazzi Maruan Hijazi Conrad Bessant Pedro R Cutillas Community detection in empirical kinase networks identifies new potential members of signalling pathways. PLoS Computational Biology |
| title | Community detection in empirical kinase networks identifies new potential members of signalling pathways. |
| title_full | Community detection in empirical kinase networks identifies new potential members of signalling pathways. |
| title_fullStr | Community detection in empirical kinase networks identifies new potential members of signalling pathways. |
| title_full_unstemmed | Community detection in empirical kinase networks identifies new potential members of signalling pathways. |
| title_short | Community detection in empirical kinase networks identifies new potential members of signalling pathways. |
| title_sort | community detection in empirical kinase networks identifies new potential members of signalling pathways |
| url | https://doi.org/10.1371/journal.pcbi.1010459 |
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