Functional selectivity of Receptor Tyrosine Kinases regulates distinct cellular outputs
Functional selectivity refers to the activation of differential signalling and cellular outputs downstream of the same membrane-bound receptor when activated by two or more different ligands. Functional selectivity has been described and extensively studied for G-protein Coupled Receptors (GPCRs), l...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2024-01-01
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| Series: | Frontiers in Cell and Developmental Biology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fcell.2023.1348056/full |
| _version_ | 1797362508596510720 |
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| author | Sakim S. Samad Sakim S. Samad Jean-Marc Schwartz Chiara Francavilla Chiara Francavilla |
| author_facet | Sakim S. Samad Sakim S. Samad Jean-Marc Schwartz Chiara Francavilla Chiara Francavilla |
| author_sort | Sakim S. Samad |
| collection | DOAJ |
| description | Functional selectivity refers to the activation of differential signalling and cellular outputs downstream of the same membrane-bound receptor when activated by two or more different ligands. Functional selectivity has been described and extensively studied for G-protein Coupled Receptors (GPCRs), leading to specific therapeutic options for dysregulated GPCRs functions. However, studies regarding the functional selectivity of Receptor Tyrosine Kinases (RTKs) remain sparse. Here, we will summarize recent data about RTK functional selectivity focusing on how the nature and the amount of RTK ligands and the crosstalk of RTKs with other membrane proteins regulate the specificity of RTK signalling. In addition, we will discuss how structural changes in RTKs upon ligand binding affects selective signalling pathways. Much remains to be known about the integration of different signals affecting RTK signalling specificity to orchestrate long-term cellular outcomes. Recent advancements in omics, specifically quantitative phosphoproteomics, and in systems biology methods to study, model and integrate different types of large-scale omics data have increased our ability to compare several signals affecting RTK functional selectivity in a global, system-wide fashion. We will discuss how such methods facilitate the exploration of important signalling hubs and enable data-driven predictions aiming at improving the efficacy of therapeutics for diseases like cancer, where redundant RTK signalling pathways often compromise treatment efficacy. |
| first_indexed | 2024-03-08T16:08:51Z |
| format | Article |
| id | doaj.art-e50b27cb4b6144808ab49302335c7b15 |
| institution | Directory Open Access Journal |
| issn | 2296-634X |
| language | English |
| last_indexed | 2024-03-08T16:08:51Z |
| publishDate | 2024-01-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Cell and Developmental Biology |
| spelling | doaj.art-e50b27cb4b6144808ab49302335c7b152024-01-08T04:31:00ZengFrontiers Media S.A.Frontiers in Cell and Developmental Biology2296-634X2024-01-011110.3389/fcell.2023.13480561348056Functional selectivity of Receptor Tyrosine Kinases regulates distinct cellular outputsSakim S. Samad0Sakim S. Samad1Jean-Marc Schwartz2Chiara Francavilla3Chiara Francavilla4Division of Molecular and Cellular Functions, School of Biological Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, United KingdomDivision of Evolution, School of Biological Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, United KingdomDivision of Evolution, School of Biological Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, United KingdomDivision of Molecular and Cellular Functions, School of Biological Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, United KingdomSection of Protein Science and Biotherapeutics, Department of Bioengineering and Biomedicine, Danish Technical University, Lyngby, DenmarkFunctional selectivity refers to the activation of differential signalling and cellular outputs downstream of the same membrane-bound receptor when activated by two or more different ligands. Functional selectivity has been described and extensively studied for G-protein Coupled Receptors (GPCRs), leading to specific therapeutic options for dysregulated GPCRs functions. However, studies regarding the functional selectivity of Receptor Tyrosine Kinases (RTKs) remain sparse. Here, we will summarize recent data about RTK functional selectivity focusing on how the nature and the amount of RTK ligands and the crosstalk of RTKs with other membrane proteins regulate the specificity of RTK signalling. In addition, we will discuss how structural changes in RTKs upon ligand binding affects selective signalling pathways. Much remains to be known about the integration of different signals affecting RTK signalling specificity to orchestrate long-term cellular outcomes. Recent advancements in omics, specifically quantitative phosphoproteomics, and in systems biology methods to study, model and integrate different types of large-scale omics data have increased our ability to compare several signals affecting RTK functional selectivity in a global, system-wide fashion. We will discuss how such methods facilitate the exploration of important signalling hubs and enable data-driven predictions aiming at improving the efficacy of therapeutics for diseases like cancer, where redundant RTK signalling pathways often compromise treatment efficacy.https://www.frontiersin.org/articles/10.3389/fcell.2023.1348056/fullfunctional selectivityligand biasligand concentrationmodellingreceptor tyrosine kinase (RTK)cell signalling |
| spellingShingle | Sakim S. Samad Sakim S. Samad Jean-Marc Schwartz Chiara Francavilla Chiara Francavilla Functional selectivity of Receptor Tyrosine Kinases regulates distinct cellular outputs Frontiers in Cell and Developmental Biology functional selectivity ligand bias ligand concentration modelling receptor tyrosine kinase (RTK) cell signalling |
| title | Functional selectivity of Receptor Tyrosine Kinases regulates distinct cellular outputs |
| title_full | Functional selectivity of Receptor Tyrosine Kinases regulates distinct cellular outputs |
| title_fullStr | Functional selectivity of Receptor Tyrosine Kinases regulates distinct cellular outputs |
| title_full_unstemmed | Functional selectivity of Receptor Tyrosine Kinases regulates distinct cellular outputs |
| title_short | Functional selectivity of Receptor Tyrosine Kinases regulates distinct cellular outputs |
| title_sort | functional selectivity of receptor tyrosine kinases regulates distinct cellular outputs |
| topic | functional selectivity ligand bias ligand concentration modelling receptor tyrosine kinase (RTK) cell signalling |
| url | https://www.frontiersin.org/articles/10.3389/fcell.2023.1348056/full |
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