The docking interaction of caspase-9 with ERK2 provides a mechanism for the selective inhibitory phosphorylation of caspase-9 at threonine 125.
Caspase-9 plays a critical role in the initiation of apoptosis by the mitochondrial pathway. Activation of caspase-9 is inhibited by phosphorylation at Thr(125) by ERK1/2 MAPKs in response to growth factors. Here, we show that phosphorylation of this site is specific for these classical MAPKs and is...
| Үндсэн зохиолчид: | , , , |
|---|---|
| Формат: | Journal article |
| Хэл сонгох: | English |
| Хэвлэсэн: |
2008
|
| _version_ | 1826279428877975552 |
|---|---|
| author | Martin, M Allan, L Mancini, E Clarke, P |
| author_facet | Martin, M Allan, L Mancini, E Clarke, P |
| author_sort | Martin, M |
| collection | OXFORD |
| description | Caspase-9 plays a critical role in the initiation of apoptosis by the mitochondrial pathway. Activation of caspase-9 is inhibited by phosphorylation at Thr(125) by ERK1/2 MAPKs in response to growth factors. Here, we show that phosphorylation of this site is specific for these classical MAPKs and is not strongly induced when JNK and p38alpha/beta MAPKs are activated by anisomycin. By deletion and mutagenic analysis, we identify domains in caspase-9 and ERK2 that mediate their interaction. Binding of ERK2 to caspase-9 and subsequent phosphorylation of caspase-9 requires a basic docking domain (D domain) in the N-terminal prodomain of the caspase. Mutational analysis of ERK2 reveals a (157)TTCD(160) motif required for recognition of caspase-9 that acts independently of the putative common docking domain. Molecular modeling supports the conclusion that Arg(10) in the D domain of caspase-9 interacts with Asp(160) in the TTCD motif of ERK2. Differences in the TTCD motif in other MAPK family members could account for the selective recognition of caspase-9 by ERK1/2. This selectivity may be important for the antiapoptotic role of classical MAPKs in contrast to the proapoptotic roles of stress-activated MAPKs. |
| first_indexed | 2024-03-06T23:58:35Z |
| format | Journal article |
| id | oxford-uuid:751b9165-0970-4621-b3c2-e738bb13eaf2 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-06T23:58:35Z |
| publishDate | 2008 |
| record_format | dspace |
| spelling | oxford-uuid:751b9165-0970-4621-b3c2-e738bb13eaf22022-03-26T20:07:21ZThe docking interaction of caspase-9 with ERK2 provides a mechanism for the selective inhibitory phosphorylation of caspase-9 at threonine 125.Journal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:751b9165-0970-4621-b3c2-e738bb13eaf2EnglishSymplectic Elements at Oxford2008Martin, MAllan, LMancini, EClarke, PCaspase-9 plays a critical role in the initiation of apoptosis by the mitochondrial pathway. Activation of caspase-9 is inhibited by phosphorylation at Thr(125) by ERK1/2 MAPKs in response to growth factors. Here, we show that phosphorylation of this site is specific for these classical MAPKs and is not strongly induced when JNK and p38alpha/beta MAPKs are activated by anisomycin. By deletion and mutagenic analysis, we identify domains in caspase-9 and ERK2 that mediate their interaction. Binding of ERK2 to caspase-9 and subsequent phosphorylation of caspase-9 requires a basic docking domain (D domain) in the N-terminal prodomain of the caspase. Mutational analysis of ERK2 reveals a (157)TTCD(160) motif required for recognition of caspase-9 that acts independently of the putative common docking domain. Molecular modeling supports the conclusion that Arg(10) in the D domain of caspase-9 interacts with Asp(160) in the TTCD motif of ERK2. Differences in the TTCD motif in other MAPK family members could account for the selective recognition of caspase-9 by ERK1/2. This selectivity may be important for the antiapoptotic role of classical MAPKs in contrast to the proapoptotic roles of stress-activated MAPKs. |
| spellingShingle | Martin, M Allan, L Mancini, E Clarke, P The docking interaction of caspase-9 with ERK2 provides a mechanism for the selective inhibitory phosphorylation of caspase-9 at threonine 125. |
| title | The docking interaction of caspase-9 with ERK2 provides a mechanism for the selective inhibitory phosphorylation of caspase-9 at threonine 125. |
| title_full | The docking interaction of caspase-9 with ERK2 provides a mechanism for the selective inhibitory phosphorylation of caspase-9 at threonine 125. |
| title_fullStr | The docking interaction of caspase-9 with ERK2 provides a mechanism for the selective inhibitory phosphorylation of caspase-9 at threonine 125. |
| title_full_unstemmed | The docking interaction of caspase-9 with ERK2 provides a mechanism for the selective inhibitory phosphorylation of caspase-9 at threonine 125. |
| title_short | The docking interaction of caspase-9 with ERK2 provides a mechanism for the selective inhibitory phosphorylation of caspase-9 at threonine 125. |
| title_sort | docking interaction of caspase 9 with erk2 provides a mechanism for the selective inhibitory phosphorylation of caspase 9 at threonine 125 |
| work_keys_str_mv | AT martinm thedockinginteractionofcaspase9witherk2providesamechanismfortheselectiveinhibitoryphosphorylationofcaspase9atthreonine125 AT allanl thedockinginteractionofcaspase9witherk2providesamechanismfortheselectiveinhibitoryphosphorylationofcaspase9atthreonine125 AT mancinie thedockinginteractionofcaspase9witherk2providesamechanismfortheselectiveinhibitoryphosphorylationofcaspase9atthreonine125 AT clarkep thedockinginteractionofcaspase9witherk2providesamechanismfortheselectiveinhibitoryphosphorylationofcaspase9atthreonine125 AT martinm dockinginteractionofcaspase9witherk2providesamechanismfortheselectiveinhibitoryphosphorylationofcaspase9atthreonine125 AT allanl dockinginteractionofcaspase9witherk2providesamechanismfortheselectiveinhibitoryphosphorylationofcaspase9atthreonine125 AT mancinie dockinginteractionofcaspase9witherk2providesamechanismfortheselectiveinhibitoryphosphorylationofcaspase9atthreonine125 AT clarkep dockinginteractionofcaspase9witherk2providesamechanismfortheselectiveinhibitoryphosphorylationofcaspase9atthreonine125 |