Crosstalk and signalling switches in mitogen-activated protein kinase cascades
Mitogen-activated protein kinase (MAPK) cascades control cell fate decisions, such as proliferation, differentiation and apoptosis by integrating and processing intra- and extracellular cues. However, similar MAPK kinetic profiles can be associated with opposing cellular decisions depending on cell...
| Main Authors: | , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2012-09-01
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| Series: | Frontiers in Physiology |
| Subjects: | |
| Online Access: | http://journal.frontiersin.org/Journal/10.3389/fphys.2012.00355/full |
| _version_ | 1818562496338853888 |
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| author | Dirk eFey David R Croucher Walter eKolch Boris N Kholodenko |
| author_facet | Dirk eFey David R Croucher Walter eKolch Boris N Kholodenko |
| author_sort | Dirk eFey |
| collection | DOAJ |
| description | Mitogen-activated protein kinase (MAPK) cascades control cell fate decisions, such as proliferation, differentiation and apoptosis by integrating and processing intra- and extracellular cues. However, similar MAPK kinetic profiles can be associated with opposing cellular decisions depending on cell type, signal strength and dynamics. This implies that signalling by each individual MAPK cascade has to be considered in the context of the entire MAPK network. Here, we develop a dynamic model of feedback and crosstalk for the three major MAPK cascades; extracellular signal-regulated kinase (ERK), p38 mitogen-activated protein kinase (p38), c-Jun N-terminal kinase (JNK), and also include input from protein kinase B (AKT). Focusing on the bistable activation characteristics of the JNK pathway, this model explains how pathway crosstalk harmonises different MAPK responses resulting in pivotal cell fate decisions. We show that JNK can switch from a transient to sustained activity due to multiple positive feedback loops. Once activated, positive feedback locks JNK in a highly active state and promotes cell death. The switch is modulated by the ERK, p38 and AKT pathways. ERK activation enhances the dual specificity phosphatase (DUSP) mediated dephosphorylation of JNK and shifts the threshold of the apoptotic switch to higher inputs. Activation of p38 restores the threshold by inhibiting ERK activity via the PP1 or PP2A phosphatases. Finally, AKT activation inhibits the JNK positive feedback, thus abrogating the apoptotic switch and allowing only proliferative signalling. Our model facilitates understanding of how cancerous deregulations disturb MAPK signal processing and provides explanations for certain drug resistances. We highlight a critical role of DUSP1 and DUSP2 expression patterns in facilitating the switching of JNK activity and show how oncogene induced ERK hyperactivity prevents the normal apoptotic switch explaining the failure ocertain drugs to induce apoptosis. |
| first_indexed | 2024-12-14T01:04:30Z |
| format | Article |
| id | doaj.art-61c07fe841874d88929f33fef7ad3247 |
| institution | Directory Open Access Journal |
| issn | 1664-042X |
| language | English |
| last_indexed | 2024-12-14T01:04:30Z |
| publishDate | 2012-09-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Physiology |
| spelling | doaj.art-61c07fe841874d88929f33fef7ad32472022-12-21T23:23:03ZengFrontiers Media S.A.Frontiers in Physiology1664-042X2012-09-01310.3389/fphys.2012.0035531406Crosstalk and signalling switches in mitogen-activated protein kinase cascadesDirk eFey0David R Croucher1Walter eKolch2Boris N Kholodenko3University College DublinUniversity College DublinUniversity College DublinUniversity College DublinMitogen-activated protein kinase (MAPK) cascades control cell fate decisions, such as proliferation, differentiation and apoptosis by integrating and processing intra- and extracellular cues. However, similar MAPK kinetic profiles can be associated with opposing cellular decisions depending on cell type, signal strength and dynamics. This implies that signalling by each individual MAPK cascade has to be considered in the context of the entire MAPK network. Here, we develop a dynamic model of feedback and crosstalk for the three major MAPK cascades; extracellular signal-regulated kinase (ERK), p38 mitogen-activated protein kinase (p38), c-Jun N-terminal kinase (JNK), and also include input from protein kinase B (AKT). Focusing on the bistable activation characteristics of the JNK pathway, this model explains how pathway crosstalk harmonises different MAPK responses resulting in pivotal cell fate decisions. We show that JNK can switch from a transient to sustained activity due to multiple positive feedback loops. Once activated, positive feedback locks JNK in a highly active state and promotes cell death. The switch is modulated by the ERK, p38 and AKT pathways. ERK activation enhances the dual specificity phosphatase (DUSP) mediated dephosphorylation of JNK and shifts the threshold of the apoptotic switch to higher inputs. Activation of p38 restores the threshold by inhibiting ERK activity via the PP1 or PP2A phosphatases. Finally, AKT activation inhibits the JNK positive feedback, thus abrogating the apoptotic switch and allowing only proliferative signalling. Our model facilitates understanding of how cancerous deregulations disturb MAPK signal processing and provides explanations for certain drug resistances. We highlight a critical role of DUSP1 and DUSP2 expression patterns in facilitating the switching of JNK activity and show how oncogene induced ERK hyperactivity prevents the normal apoptotic switch explaining the failure ocertain drugs to induce apoptosis.http://journal.frontiersin.org/Journal/10.3389/fphys.2012.00355/fullJNK Mitogen-Activated Protein KinasesAkt (PKBbistabilitydynamic modelDual specificity phosphatase (DUSP) |
| spellingShingle | Dirk eFey David R Croucher Walter eKolch Boris N Kholodenko Crosstalk and signalling switches in mitogen-activated protein kinase cascades Frontiers in Physiology JNK Mitogen-Activated Protein Kinases Akt (PKB bistability dynamic model Dual specificity phosphatase (DUSP) |
| title | Crosstalk and signalling switches in mitogen-activated protein kinase cascades |
| title_full | Crosstalk and signalling switches in mitogen-activated protein kinase cascades |
| title_fullStr | Crosstalk and signalling switches in mitogen-activated protein kinase cascades |
| title_full_unstemmed | Crosstalk and signalling switches in mitogen-activated protein kinase cascades |
| title_short | Crosstalk and signalling switches in mitogen-activated protein kinase cascades |
| title_sort | crosstalk and signalling switches in mitogen activated protein kinase cascades |
| topic | JNK Mitogen-Activated Protein Kinases Akt (PKB bistability dynamic model Dual specificity phosphatase (DUSP) |
| url | http://journal.frontiersin.org/Journal/10.3389/fphys.2012.00355/full |
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