Theoretical analysis reveals a role for RAF conformational autoinhibition in paradoxical activation
RAF kinase inhibitors can, under certain conditions, increase RAF kinase signaling. This process, which is commonly referred to as ‘paradoxical activation’ (PA), is incompletely understood. We use mathematical and computational modeling to investigate PA and derive rigorous analytical expressions th...
| Main Authors: | , |
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2023-10-01
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| Series: | eLife |
| Subjects: | |
| Online Access: | https://elifesciences.org/articles/82739 |
| _version_ | 1797635631868805120 |
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| author | Gaurav Mendiratta Edward Stites |
| author_facet | Gaurav Mendiratta Edward Stites |
| author_sort | Gaurav Mendiratta |
| collection | DOAJ |
| description | RAF kinase inhibitors can, under certain conditions, increase RAF kinase signaling. This process, which is commonly referred to as ‘paradoxical activation’ (PA), is incompletely understood. We use mathematical and computational modeling to investigate PA and derive rigorous analytical expressions that illuminate the underlying mechanism of this complex phenomenon. We find that conformational autoinhibition modulation by a RAF inhibitor could be sufficient to create PA. We find that experimental RAF inhibitor drug dose–response data that characterize PA across different types of RAF inhibitors are best explained by a model that includes RAF inhibitor modulation of three properties: conformational autoinhibition, dimer affinity, and drug binding within the dimer (i.e., negative cooperativity). Overall, this work establishes conformational autoinhibition as a robust mechanism for RAF inhibitor-driven PA based solely on equilibrium dynamics of canonical interactions that comprise RAF signaling and inhibition. |
| first_indexed | 2024-03-11T12:23:11Z |
| format | Article |
| id | doaj.art-e047fee18dbe4f70a428d3246f9cc35d |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-03-11T12:23:11Z |
| publishDate | 2023-10-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-e047fee18dbe4f70a428d3246f9cc35d2023-11-06T17:27:06ZengeLife Sciences Publications LtdeLife2050-084X2023-10-011210.7554/eLife.82739Theoretical analysis reveals a role for RAF conformational autoinhibition in paradoxical activationGaurav Mendiratta0https://orcid.org/0000-0001-5091-348XEdward Stites1https://orcid.org/0000-0002-3783-7336Integrative Biology Laboratory, Salk Institute for Biological Studies, La Jolla, United StatesDepartment of Laboratory Medicine, Yale University, New Haven, United States; Yale Cancer Center, Yale School of Medicine, New Haven, United StatesRAF kinase inhibitors can, under certain conditions, increase RAF kinase signaling. This process, which is commonly referred to as ‘paradoxical activation’ (PA), is incompletely understood. We use mathematical and computational modeling to investigate PA and derive rigorous analytical expressions that illuminate the underlying mechanism of this complex phenomenon. We find that conformational autoinhibition modulation by a RAF inhibitor could be sufficient to create PA. We find that experimental RAF inhibitor drug dose–response data that characterize PA across different types of RAF inhibitors are best explained by a model that includes RAF inhibitor modulation of three properties: conformational autoinhibition, dimer affinity, and drug binding within the dimer (i.e., negative cooperativity). Overall, this work establishes conformational autoinhibition as a robust mechanism for RAF inhibitor-driven PA based solely on equilibrium dynamics of canonical interactions that comprise RAF signaling and inhibition.https://elifesciences.org/articles/82739systems modelingcomputationalsystems pharmacologyprotein kinasedimerization |
| spellingShingle | Gaurav Mendiratta Edward Stites Theoretical analysis reveals a role for RAF conformational autoinhibition in paradoxical activation eLife systems modeling computational systems pharmacology protein kinase dimerization |
| title | Theoretical analysis reveals a role for RAF conformational autoinhibition in paradoxical activation |
| title_full | Theoretical analysis reveals a role for RAF conformational autoinhibition in paradoxical activation |
| title_fullStr | Theoretical analysis reveals a role for RAF conformational autoinhibition in paradoxical activation |
| title_full_unstemmed | Theoretical analysis reveals a role for RAF conformational autoinhibition in paradoxical activation |
| title_short | Theoretical analysis reveals a role for RAF conformational autoinhibition in paradoxical activation |
| title_sort | theoretical analysis reveals a role for raf conformational autoinhibition in paradoxical activation |
| topic | systems modeling computational systems pharmacology protein kinase dimerization |
| url | https://elifesciences.org/articles/82739 |
| work_keys_str_mv | AT gauravmendiratta theoreticalanalysisrevealsaroleforrafconformationalautoinhibitioninparadoxicalactivation AT edwardstites theoreticalanalysisrevealsaroleforrafconformationalautoinhibitioninparadoxicalactivation |