Relating individual cell division events to single-cell ERK and Akt activity time courses
Abstract Biochemical correlates of stochastic single-cell fates have been elusive, even for the well-studied mammalian cell cycle. We monitored single-cell dynamics of the ERK and Akt pathways, critical cell cycle progression hubs and anti-cancer drug targets, and paired them to division events in t...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2022-10-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-022-23071-6 |
| _version_ | 1811335041897201664 |
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| author | Alan D. Stern Gregory R. Smith Luis C. Santos Deepraj Sarmah Xiang Zhang Xiaoming Lu Federico Iuricich Gaurav Pandey Ravi Iyengar Marc R. Birtwistle |
| author_facet | Alan D. Stern Gregory R. Smith Luis C. Santos Deepraj Sarmah Xiang Zhang Xiaoming Lu Federico Iuricich Gaurav Pandey Ravi Iyengar Marc R. Birtwistle |
| author_sort | Alan D. Stern |
| collection | DOAJ |
| description | Abstract Biochemical correlates of stochastic single-cell fates have been elusive, even for the well-studied mammalian cell cycle. We monitored single-cell dynamics of the ERK and Akt pathways, critical cell cycle progression hubs and anti-cancer drug targets, and paired them to division events in the same single cells using the non-transformed MCF10A epithelial line. Following growth factor treatment, in cells that divide both ERK and Akt activities are significantly higher within the S-G2 time window (~ 8.5–40 h). Such differences were much smaller in the pre-S-phase, restriction point window which is traditionally associated with ERK and Akt activity dependence, suggesting unappreciated roles for ERK and Akt in S through G2. Simple metrics of central tendency in this time window are associated with subsequent cell division fates. ERK activity was more strongly associated with division fates than Akt activity, suggesting Akt activity dynamics may contribute less to the decision driving cell division in this context. We also find that ERK and Akt activities are less correlated with each other in cells that divide. Network reconstruction experiments demonstrated that this correlation behavior was likely not due to crosstalk, as ERK and Akt do not interact in this context, in contrast to other transformed cell types. Overall, our findings support roles for ERK and Akt activity throughout the cell cycle as opposed to just before the restriction point, and suggest ERK activity dynamics may be more important than Akt activity dynamics for driving cell division in this non-transformed context. |
| first_indexed | 2024-04-13T17:18:07Z |
| format | Article |
| id | doaj.art-0e672cd6d8754b4abdd87327793d54e1 |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-04-13T17:18:07Z |
| publishDate | 2022-10-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj.art-0e672cd6d8754b4abdd87327793d54e12022-12-22T02:38:04ZengNature PortfolioScientific Reports2045-23222022-10-0112111310.1038/s41598-022-23071-6Relating individual cell division events to single-cell ERK and Akt activity time coursesAlan D. Stern0Gregory R. Smith1Luis C. Santos2Deepraj Sarmah3Xiang Zhang4Xiaoming Lu5Federico Iuricich6Gaurav Pandey7Ravi Iyengar8Marc R. Birtwistle9Department of Pharmacological Sciences, Icahn School of Medicine at Mount SinaiDepartment of Neurology, Center for Advanced Research on Diagnostic Assays, Icahn School of Medicine at Mount SinaiDepartment of Pharmacological Sciences, Icahn School of Medicine at Mount SinaiDepartment of Chemical and Biomolecular Engineering, Clemson UniversitySchool of Computing, Clemson UniversityDepartment of Chemical and Biomolecular Engineering, Clemson UniversitySchool of Computing, Clemson UniversityDepartment of Genetics and Genomic Sciences, Icahn School of Medicine at Mount SinaiDepartment of Pharmacological Sciences, Icahn School of Medicine at Mount SinaiDepartment of Pharmacological Sciences, Icahn School of Medicine at Mount SinaiAbstract Biochemical correlates of stochastic single-cell fates have been elusive, even for the well-studied mammalian cell cycle. We monitored single-cell dynamics of the ERK and Akt pathways, critical cell cycle progression hubs and anti-cancer drug targets, and paired them to division events in the same single cells using the non-transformed MCF10A epithelial line. Following growth factor treatment, in cells that divide both ERK and Akt activities are significantly higher within the S-G2 time window (~ 8.5–40 h). Such differences were much smaller in the pre-S-phase, restriction point window which is traditionally associated with ERK and Akt activity dependence, suggesting unappreciated roles for ERK and Akt in S through G2. Simple metrics of central tendency in this time window are associated with subsequent cell division fates. ERK activity was more strongly associated with division fates than Akt activity, suggesting Akt activity dynamics may contribute less to the decision driving cell division in this context. We also find that ERK and Akt activities are less correlated with each other in cells that divide. Network reconstruction experiments demonstrated that this correlation behavior was likely not due to crosstalk, as ERK and Akt do not interact in this context, in contrast to other transformed cell types. Overall, our findings support roles for ERK and Akt activity throughout the cell cycle as opposed to just before the restriction point, and suggest ERK activity dynamics may be more important than Akt activity dynamics for driving cell division in this non-transformed context.https://doi.org/10.1038/s41598-022-23071-6 |
| spellingShingle | Alan D. Stern Gregory R. Smith Luis C. Santos Deepraj Sarmah Xiang Zhang Xiaoming Lu Federico Iuricich Gaurav Pandey Ravi Iyengar Marc R. Birtwistle Relating individual cell division events to single-cell ERK and Akt activity time courses Scientific Reports |
| title | Relating individual cell division events to single-cell ERK and Akt activity time courses |
| title_full | Relating individual cell division events to single-cell ERK and Akt activity time courses |
| title_fullStr | Relating individual cell division events to single-cell ERK and Akt activity time courses |
| title_full_unstemmed | Relating individual cell division events to single-cell ERK and Akt activity time courses |
| title_short | Relating individual cell division events to single-cell ERK and Akt activity time courses |
| title_sort | relating individual cell division events to single cell erk and akt activity time courses |
| url | https://doi.org/10.1038/s41598-022-23071-6 |
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