USP15 regulates SMURF2 kinetics through C-lobe mediated deubiquitination
Ubiquitin modification of the TGF-ß pathway components is emerging as a key mechanism of TGF-ß pathway regulation. To limit TGF-ß responses, TGF-ß signaling is regulated through a negative feedback loop whereby the E3 ligase SMURF2 targets the TGF-ß receptor (TßR) complex for ubiquitin-mediated degr...
| Main Authors: | , , , , , , , , |
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| Format: | Journal Article |
| Published: |
Nature Publishing Group
2015
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| Online Access: | http://hdl.handle.net/20.500.11937/73022 |
| _version_ | 1848762903319019520 |
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| author | Iyengar, P. Jaynes, P. Rodon, L. Lama, D. Law, K. Lim, Y. Verma, C. Seoane, J. Eichhorn, Pieter |
| author_facet | Iyengar, P. Jaynes, P. Rodon, L. Lama, D. Law, K. Lim, Y. Verma, C. Seoane, J. Eichhorn, Pieter |
| author_sort | Iyengar, P. |
| building | Curtin Institutional Repository |
| collection | Online Access |
| description | Ubiquitin modification of the TGF-ß pathway components is emerging as a key mechanism of TGF-ß pathway regulation. To limit TGF-ß responses, TGF-ß signaling is regulated through a negative feedback loop whereby the E3 ligase SMURF2 targets the TGF-ß receptor (TßR) complex for ubiquitin-mediated degradation. Counteracting this process, a number of deubiquitinating (DUBs) enzymes have recently been identified that deubiquitinate and stabilize the TßR. However the precise mechanism by which these DUBs act on TßR function remains poorly defined. Here, we demonstrate that apart from targeting the TßR complex directly, USP15 also deubiquitinates SMURF2 resulting in enhanced TßR stability and downstream pathway activation. Through proteomic analysis, we show that USP15 modulates the ubiquitination of Lys734, a residue required for SMURF2 catalytic activity. Our results show that SMURF2 is a critical target of USP15 in the TGF-ß pathway and may also explain how USP15 and SMURF2 target multiple complementary protein complexes in other pathways. |
| first_indexed | 2025-11-14T10:54:57Z |
| format | Journal Article |
| id | curtin-20.500.11937-73022 |
| institution | Curtin University Malaysia |
| institution_category | Local University |
| last_indexed | 2025-11-14T10:54:57Z |
| publishDate | 2015 |
| publisher | Nature Publishing Group |
| recordtype | eprints |
| repository_type | Digital Repository |
| spelling | curtin-20.500.11937-730222019-07-08T08:29:00Z USP15 regulates SMURF2 kinetics through C-lobe mediated deubiquitination Iyengar, P. Jaynes, P. Rodon, L. Lama, D. Law, K. Lim, Y. Verma, C. Seoane, J. Eichhorn, Pieter Ubiquitin modification of the TGF-ß pathway components is emerging as a key mechanism of TGF-ß pathway regulation. To limit TGF-ß responses, TGF-ß signaling is regulated through a negative feedback loop whereby the E3 ligase SMURF2 targets the TGF-ß receptor (TßR) complex for ubiquitin-mediated degradation. Counteracting this process, a number of deubiquitinating (DUBs) enzymes have recently been identified that deubiquitinate and stabilize the TßR. However the precise mechanism by which these DUBs act on TßR function remains poorly defined. Here, we demonstrate that apart from targeting the TßR complex directly, USP15 also deubiquitinates SMURF2 resulting in enhanced TßR stability and downstream pathway activation. Through proteomic analysis, we show that USP15 modulates the ubiquitination of Lys734, a residue required for SMURF2 catalytic activity. Our results show that SMURF2 is a critical target of USP15 in the TGF-ß pathway and may also explain how USP15 and SMURF2 target multiple complementary protein complexes in other pathways. 2015 Journal Article http://hdl.handle.net/20.500.11937/73022 10.1038/srep14733 http://creativecommons.org/licenses/by/4.0/ Nature Publishing Group unknown |
| spellingShingle | Iyengar, P. Jaynes, P. Rodon, L. Lama, D. Law, K. Lim, Y. Verma, C. Seoane, J. Eichhorn, Pieter USP15 regulates SMURF2 kinetics through C-lobe mediated deubiquitination |
| title | USP15 regulates SMURF2 kinetics through C-lobe mediated deubiquitination |
| title_full | USP15 regulates SMURF2 kinetics through C-lobe mediated deubiquitination |
| title_fullStr | USP15 regulates SMURF2 kinetics through C-lobe mediated deubiquitination |
| title_full_unstemmed | USP15 regulates SMURF2 kinetics through C-lobe mediated deubiquitination |
| title_short | USP15 regulates SMURF2 kinetics through C-lobe mediated deubiquitination |
| title_sort | usp15 regulates smurf2 kinetics through c-lobe mediated deubiquitination |
| url | http://hdl.handle.net/20.500.11937/73022 |