A homeostatic model of IκB metabolism to control constitutive NF‐κB activity
Abstract Cellular signal transduction pathways are usually studied following administration of an external stimulus. However, disease‐associated aberrant activity of the pathway is often due to misregulation of the equilibrium state. The transcription factor NF‐κB is typically described as being hel...
Saved in:
| Main Authors: | , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Springer Nature
2007-05-01
|
| Series: | Molecular Systems Biology |
| Subjects: | |
| Online Access: | https://doi.org/10.1038/msb4100148 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1849225782070607872 |
|---|---|
| author | Ellen L O'Dea Derren Barken Raechel Q Peralta Kim T Tran Shannon L Werner Jeffrey D Kearns Andre Levchenko Alexander Hoffmann |
| author_facet | Ellen L O'Dea Derren Barken Raechel Q Peralta Kim T Tran Shannon L Werner Jeffrey D Kearns Andre Levchenko Alexander Hoffmann |
| author_sort | Ellen L O'Dea |
| collection | DOAJ |
| description | Abstract Cellular signal transduction pathways are usually studied following administration of an external stimulus. However, disease‐associated aberrant activity of the pathway is often due to misregulation of the equilibrium state. The transcription factor NF‐κB is typically described as being held inactive in the cytoplasm by binding its inhibitor, IκB, until an external stimulus triggers IκB degradation through an IκB kinase‐dependent degradation pathway. Combining genetic, biochemical, and computational tools, we investigate steady‐state regulation of the NF‐κB signaling module and its impact on stimulus responsiveness. We present newly measured in vivo degradation rate constants for NF‐κB‐bound and ‐unbound IκB proteins that are critical for accurate computational predictions of steady‐state IκB protein levels and basal NF‐κB activity. Simulations reveal a homeostatic NF‐κB signaling module in which differential degradation rates of free and bound pools of IκB represent a novel cross‐regulation mechanism that imparts functional robustness to the signaling module. |
| format | Article |
| id | doaj-art-9dcbccd4ddc74519890f88eb4c2cdda2 |
| institution | Kabale University |
| issn | 1744-4292 |
| language | English |
| publishDate | 2007-05-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | Molecular Systems Biology |
| spelling | doaj-art-9dcbccd4ddc74519890f88eb4c2cdda22025-08-24T12:02:05ZengSpringer NatureMolecular Systems Biology1744-42922007-05-01311710.1038/msb4100148A homeostatic model of IκB metabolism to control constitutive NF‐κB activityEllen L O'Dea0Derren Barken1Raechel Q Peralta2Kim T Tran3Shannon L Werner4Jeffrey D Kearns5Andre Levchenko6Alexander Hoffmann7Signaling Systems Laboratory, Department of Chemistry and Biochemistry, UCSDSignaling Systems Laboratory, Department of Chemistry and Biochemistry, UCSDSignaling Systems Laboratory, Department of Chemistry and Biochemistry, UCSDSignaling Systems Laboratory, Department of Chemistry and Biochemistry, UCSDSignaling Systems Laboratory, Department of Chemistry and Biochemistry, UCSDSignaling Systems Laboratory, Department of Chemistry and Biochemistry, UCSDDepartment of Biomedical Engineering, Johns Hopkins UniversitySignaling Systems Laboratory, Department of Chemistry and Biochemistry, UCSDAbstract Cellular signal transduction pathways are usually studied following administration of an external stimulus. However, disease‐associated aberrant activity of the pathway is often due to misregulation of the equilibrium state. The transcription factor NF‐κB is typically described as being held inactive in the cytoplasm by binding its inhibitor, IκB, until an external stimulus triggers IκB degradation through an IκB kinase‐dependent degradation pathway. Combining genetic, biochemical, and computational tools, we investigate steady‐state regulation of the NF‐κB signaling module and its impact on stimulus responsiveness. We present newly measured in vivo degradation rate constants for NF‐κB‐bound and ‐unbound IκB proteins that are critical for accurate computational predictions of steady‐state IκB protein levels and basal NF‐κB activity. Simulations reveal a homeostatic NF‐κB signaling module in which differential degradation rates of free and bound pools of IκB represent a novel cross‐regulation mechanism that imparts functional robustness to the signaling module.https://doi.org/10.1038/msb4100148cross‐regulationhomeostasismathematical modelingrobustnesssignaling module |
| spellingShingle | Ellen L O'Dea Derren Barken Raechel Q Peralta Kim T Tran Shannon L Werner Jeffrey D Kearns Andre Levchenko Alexander Hoffmann A homeostatic model of IκB metabolism to control constitutive NF‐κB activity Molecular Systems Biology cross‐regulation homeostasis mathematical modeling robustness signaling module |
| title | A homeostatic model of IκB metabolism to control constitutive NF‐κB activity |
| title_full | A homeostatic model of IκB metabolism to control constitutive NF‐κB activity |
| title_fullStr | A homeostatic model of IκB metabolism to control constitutive NF‐κB activity |
| title_full_unstemmed | A homeostatic model of IκB metabolism to control constitutive NF‐κB activity |
| title_short | A homeostatic model of IκB metabolism to control constitutive NF‐κB activity |
| title_sort | homeostatic model of iκb metabolism to control constitutive nf κb activity |
| topic | cross‐regulation homeostasis mathematical modeling robustness signaling module |
| url | https://doi.org/10.1038/msb4100148 |
| work_keys_str_mv | AT ellenlodea ahomeostaticmodelofikbmetabolismtocontrolconstitutivenfkbactivity AT derrenbarken ahomeostaticmodelofikbmetabolismtocontrolconstitutivenfkbactivity AT raechelqperalta ahomeostaticmodelofikbmetabolismtocontrolconstitutivenfkbactivity AT kimttran ahomeostaticmodelofikbmetabolismtocontrolconstitutivenfkbactivity AT shannonlwerner ahomeostaticmodelofikbmetabolismtocontrolconstitutivenfkbactivity AT jeffreydkearns ahomeostaticmodelofikbmetabolismtocontrolconstitutivenfkbactivity AT andrelevchenko ahomeostaticmodelofikbmetabolismtocontrolconstitutivenfkbactivity AT alexanderhoffmann ahomeostaticmodelofikbmetabolismtocontrolconstitutivenfkbactivity AT ellenlodea homeostaticmodelofikbmetabolismtocontrolconstitutivenfkbactivity AT derrenbarken homeostaticmodelofikbmetabolismtocontrolconstitutivenfkbactivity AT raechelqperalta homeostaticmodelofikbmetabolismtocontrolconstitutivenfkbactivity AT kimttran homeostaticmodelofikbmetabolismtocontrolconstitutivenfkbactivity AT shannonlwerner homeostaticmodelofikbmetabolismtocontrolconstitutivenfkbactivity AT jeffreydkearns homeostaticmodelofikbmetabolismtocontrolconstitutivenfkbactivity AT andrelevchenko homeostaticmodelofikbmetabolismtocontrolconstitutivenfkbactivity AT alexanderhoffmann homeostaticmodelofikbmetabolismtocontrolconstitutivenfkbactivity |