Phosphorylation of iRhom2 at the plasma membrane controls mammalian TACE-dependent inflammatory and growth factor signalling.
Proteolytic cleavage and release from the cell surface of membrane-tethered ligands is an important mechanism of regulating intercellular signalling. TACE is a major shedding protease, responsible for the liberation of the inflammatory cytokine TNFα and ligands of the epidermal growth factor recepto...
| Main Authors: | , , , , , |
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| Format: | Journal article |
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eLife Sciences Publications
2017
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| _version_ | 1797067769997426688 |
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| author | Grieve, A Xu, H Künzel, U Bambrough, P Sieber, B Freeman, M |
| author_facet | Grieve, A Xu, H Künzel, U Bambrough, P Sieber, B Freeman, M |
| author_sort | Grieve, A |
| collection | OXFORD |
| description | Proteolytic cleavage and release from the cell surface of membrane-tethered ligands is an important mechanism of regulating intercellular signalling. TACE is a major shedding protease, responsible for the liberation of the inflammatory cytokine TNFα and ligands of the epidermal growth factor receptor. iRhoms, catalytically inactive members of the rhomboid-like superfamily, have been shown to control the ER-to-Golgi transport and maturation of TACE. Here, we reveal that iRhom2 remains associated with TACE throughout the secretory pathway, and is stabilised at the cell surface by this interaction. At the plasma membrane, ERK1/2-mediated phosphorylation and 14-3-3 protein binding of the cytoplasmic amino-terminus of iRhom2 alter its interaction with mature TACE, thereby licensing its proteolytic activity. We show that this molecular mechanism is responsible for triggering inflammatory responses in primary mouse macrophages. Overall, iRhom2 binds to TACE throughout its lifecycle, implying that iRhom2 is a primary regulator of stimulated cytokine and growth factor signalling. |
| first_indexed | 2024-03-06T22:01:05Z |
| format | Journal article |
| id | oxford-uuid:4e9a8f38-28e6-4603-9745-e84de9aadbef |
| institution | University of Oxford |
| last_indexed | 2024-03-06T22:01:05Z |
| publishDate | 2017 |
| publisher | eLife Sciences Publications |
| record_format | dspace |
| spelling | oxford-uuid:4e9a8f38-28e6-4603-9745-e84de9aadbef2022-03-26T16:02:10ZPhosphorylation of iRhom2 at the plasma membrane controls mammalian TACE-dependent inflammatory and growth factor signalling.Journal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:4e9a8f38-28e6-4603-9745-e84de9aadbefSymplectic Elements at OxfordeLife Sciences Publications2017Grieve, AXu, HKünzel, UBambrough, PSieber, BFreeman, MProteolytic cleavage and release from the cell surface of membrane-tethered ligands is an important mechanism of regulating intercellular signalling. TACE is a major shedding protease, responsible for the liberation of the inflammatory cytokine TNFα and ligands of the epidermal growth factor receptor. iRhoms, catalytically inactive members of the rhomboid-like superfamily, have been shown to control the ER-to-Golgi transport and maturation of TACE. Here, we reveal that iRhom2 remains associated with TACE throughout the secretory pathway, and is stabilised at the cell surface by this interaction. At the plasma membrane, ERK1/2-mediated phosphorylation and 14-3-3 protein binding of the cytoplasmic amino-terminus of iRhom2 alter its interaction with mature TACE, thereby licensing its proteolytic activity. We show that this molecular mechanism is responsible for triggering inflammatory responses in primary mouse macrophages. Overall, iRhom2 binds to TACE throughout its lifecycle, implying that iRhom2 is a primary regulator of stimulated cytokine and growth factor signalling. |
| spellingShingle | Grieve, A Xu, H Künzel, U Bambrough, P Sieber, B Freeman, M Phosphorylation of iRhom2 at the plasma membrane controls mammalian TACE-dependent inflammatory and growth factor signalling. |
| title | Phosphorylation of iRhom2 at the plasma membrane controls mammalian TACE-dependent inflammatory and growth factor signalling. |
| title_full | Phosphorylation of iRhom2 at the plasma membrane controls mammalian TACE-dependent inflammatory and growth factor signalling. |
| title_fullStr | Phosphorylation of iRhom2 at the plasma membrane controls mammalian TACE-dependent inflammatory and growth factor signalling. |
| title_full_unstemmed | Phosphorylation of iRhom2 at the plasma membrane controls mammalian TACE-dependent inflammatory and growth factor signalling. |
| title_short | Phosphorylation of iRhom2 at the plasma membrane controls mammalian TACE-dependent inflammatory and growth factor signalling. |
| title_sort | phosphorylation of irhom2 at the plasma membrane controls mammalian tace dependent inflammatory and growth factor signalling |
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