Rabex-5 E3 and Rab5 GEF domains differ in their regulation of Ras, Notch, and PI3K signaling in Drosophila wing development.
Rabex-5 (also called RabGEF1), a protein originally characterized for its Rab5 GEF function, also has an A20-like E3 ubiquitin ligase domain. We and others reported that Rabex-5 E3 activity promotes Ras mono- and di-ubiquitination to inhibit Ras signaling in Drosophila and mammals. Subsequently, we...
Saved in:
| Main Authors: | , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2024-01-01
|
| Series: | PLoS ONE |
| Online Access: | https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0312274&type=printable |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1832592692708638720 |
|---|---|
| author | Theresa A Reimels Mia Steinberg Hua Yan Sivan Shahar Ashley Rosenberg Kristina Kalafsky Max Luf Lindsay Kelly Stacia Octaviani Cathie M Pfleger |
| author_facet | Theresa A Reimels Mia Steinberg Hua Yan Sivan Shahar Ashley Rosenberg Kristina Kalafsky Max Luf Lindsay Kelly Stacia Octaviani Cathie M Pfleger |
| author_sort | Theresa A Reimels |
| collection | DOAJ |
| description | Rabex-5 (also called RabGEF1), a protein originally characterized for its Rab5 GEF function, also has an A20-like E3 ubiquitin ligase domain. We and others reported that Rabex-5 E3 activity promotes Ras mono- and di-ubiquitination to inhibit Ras signaling in Drosophila and mammals. Subsequently, we reported that Rabex-5 inhibits Notch signaling in the Drosophila hematopoietic system. Here we report genetic interactions using Rabex-5 transgenes encoding domain-specific mutations that show that Rabex-5 requires an intact E3 domain to inhibit Notch signaling in the epithelial tissue of the developing wing. Surprisingly, we discovered that Rabex-5 with an impaired E3 domain but active Rab5 GEF domain suppresses Notch loss-of-function phenotypes and enhances both Notch duplication phenotypes and activated Ras phenotypes consistent with a model that the Rab5 GEF activity of Rabex-5 might positively regulate Ras and Notch. Positive and negative regulation of developmental signaling by its different catalytic domains could allow Rabex-5 to precisely coordinate developmental signaling to fine-tune patterning. Finally, we report that Rabex-5 also inhibits the overgrowth due to loss of PTEN or activation of PI3K but not activation of AKT. Inhibition of Ras, Notch, and PI3K signaling may explain why Rabex-5 is deleted in some cancers. Paradoxically, Rabex-5 is reported to be an oncogene in other cancers. We propose that Rabex-5 acts as a tumor suppressor via its E3 activity to inhibit Ras, Notch, and PI3K signaling and as an oncogene via its Rab5 GEF activity to enhance Ras and Notch signaling. |
| format | Article |
| id | doaj-art-1948ec6193b948dd952c77dcc807546d |
| institution | Kabale University |
| issn | 1932-6203 |
| language | English |
| publishDate | 2024-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj-art-1948ec6193b948dd952c77dcc807546d2025-01-21T05:31:23ZengPublic Library of Science (PLoS)PLoS ONE1932-62032024-01-011910e031227410.1371/journal.pone.0312274Rabex-5 E3 and Rab5 GEF domains differ in their regulation of Ras, Notch, and PI3K signaling in Drosophila wing development.Theresa A ReimelsMia SteinbergHua YanSivan ShaharAshley RosenbergKristina KalafskyMax LufLindsay KellyStacia OctavianiCathie M PflegerRabex-5 (also called RabGEF1), a protein originally characterized for its Rab5 GEF function, also has an A20-like E3 ubiquitin ligase domain. We and others reported that Rabex-5 E3 activity promotes Ras mono- and di-ubiquitination to inhibit Ras signaling in Drosophila and mammals. Subsequently, we reported that Rabex-5 inhibits Notch signaling in the Drosophila hematopoietic system. Here we report genetic interactions using Rabex-5 transgenes encoding domain-specific mutations that show that Rabex-5 requires an intact E3 domain to inhibit Notch signaling in the epithelial tissue of the developing wing. Surprisingly, we discovered that Rabex-5 with an impaired E3 domain but active Rab5 GEF domain suppresses Notch loss-of-function phenotypes and enhances both Notch duplication phenotypes and activated Ras phenotypes consistent with a model that the Rab5 GEF activity of Rabex-5 might positively regulate Ras and Notch. Positive and negative regulation of developmental signaling by its different catalytic domains could allow Rabex-5 to precisely coordinate developmental signaling to fine-tune patterning. Finally, we report that Rabex-5 also inhibits the overgrowth due to loss of PTEN or activation of PI3K but not activation of AKT. Inhibition of Ras, Notch, and PI3K signaling may explain why Rabex-5 is deleted in some cancers. Paradoxically, Rabex-5 is reported to be an oncogene in other cancers. We propose that Rabex-5 acts as a tumor suppressor via its E3 activity to inhibit Ras, Notch, and PI3K signaling and as an oncogene via its Rab5 GEF activity to enhance Ras and Notch signaling.https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0312274&type=printable |
| spellingShingle | Theresa A Reimels Mia Steinberg Hua Yan Sivan Shahar Ashley Rosenberg Kristina Kalafsky Max Luf Lindsay Kelly Stacia Octaviani Cathie M Pfleger Rabex-5 E3 and Rab5 GEF domains differ in their regulation of Ras, Notch, and PI3K signaling in Drosophila wing development. PLoS ONE |
| title | Rabex-5 E3 and Rab5 GEF domains differ in their regulation of Ras, Notch, and PI3K signaling in Drosophila wing development. |
| title_full | Rabex-5 E3 and Rab5 GEF domains differ in their regulation of Ras, Notch, and PI3K signaling in Drosophila wing development. |
| title_fullStr | Rabex-5 E3 and Rab5 GEF domains differ in their regulation of Ras, Notch, and PI3K signaling in Drosophila wing development. |
| title_full_unstemmed | Rabex-5 E3 and Rab5 GEF domains differ in their regulation of Ras, Notch, and PI3K signaling in Drosophila wing development. |
| title_short | Rabex-5 E3 and Rab5 GEF domains differ in their regulation of Ras, Notch, and PI3K signaling in Drosophila wing development. |
| title_sort | rabex 5 e3 and rab5 gef domains differ in their regulation of ras notch and pi3k signaling in drosophila wing development |
| url | https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0312274&type=printable |
| work_keys_str_mv | AT theresaareimels rabex5e3andrab5gefdomainsdifferintheirregulationofrasnotchandpi3ksignalingindrosophilawingdevelopment AT miasteinberg rabex5e3andrab5gefdomainsdifferintheirregulationofrasnotchandpi3ksignalingindrosophilawingdevelopment AT huayan rabex5e3andrab5gefdomainsdifferintheirregulationofrasnotchandpi3ksignalingindrosophilawingdevelopment AT sivanshahar rabex5e3andrab5gefdomainsdifferintheirregulationofrasnotchandpi3ksignalingindrosophilawingdevelopment AT ashleyrosenberg rabex5e3andrab5gefdomainsdifferintheirregulationofrasnotchandpi3ksignalingindrosophilawingdevelopment AT kristinakalafsky rabex5e3andrab5gefdomainsdifferintheirregulationofrasnotchandpi3ksignalingindrosophilawingdevelopment AT maxluf rabex5e3andrab5gefdomainsdifferintheirregulationofrasnotchandpi3ksignalingindrosophilawingdevelopment AT lindsaykelly rabex5e3andrab5gefdomainsdifferintheirregulationofrasnotchandpi3ksignalingindrosophilawingdevelopment AT staciaoctaviani rabex5e3andrab5gefdomainsdifferintheirregulationofrasnotchandpi3ksignalingindrosophilawingdevelopment AT cathiempfleger rabex5e3andrab5gefdomainsdifferintheirregulationofrasnotchandpi3ksignalingindrosophilawingdevelopment |