The nonreceptor tyrosine kinase SRMS inhibits autophagy and promotes tumor growth by phosphorylating the scaffolding protein FKBP51.
Nutrient-responsive protein kinases control the balance between anabolic growth and catabolic processes such as autophagy. Aberrant regulation of these kinases is a major cause of human disease. We report here that the vertebrate nonreceptor tyrosine kinase Src-related kinase lacking C-terminal regu...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2021-06-01
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| Series: | PLoS Biology |
| Online Access: | https://doi.org/10.1371/journal.pbio.3001281 |
| _version_ | 1818918839182688256 |
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| author | Jung Mi Park Seung Wook Yang Wei Zhuang Asim K Bera Yan Liu Deepak Gurbani Sergei J von Hoyningen-Huene Sadie Miki Sakurada Haiyun Gan Shondra M Pruett-Miller Kenneth D Westover Malia B Potts |
| author_facet | Jung Mi Park Seung Wook Yang Wei Zhuang Asim K Bera Yan Liu Deepak Gurbani Sergei J von Hoyningen-Huene Sadie Miki Sakurada Haiyun Gan Shondra M Pruett-Miller Kenneth D Westover Malia B Potts |
| author_sort | Jung Mi Park |
| collection | DOAJ |
| description | Nutrient-responsive protein kinases control the balance between anabolic growth and catabolic processes such as autophagy. Aberrant regulation of these kinases is a major cause of human disease. We report here that the vertebrate nonreceptor tyrosine kinase Src-related kinase lacking C-terminal regulatory tyrosine and N-terminal myristylation sites (SRMS) inhibits autophagy and promotes growth in a nutrient-responsive manner. Under nutrient-replete conditions, SRMS phosphorylates the PHLPP scaffold FK506-binding protein 51 (FKBP51), disrupts the FKBP51-PHLPP complex, and promotes FKBP51 degradation through the ubiquitin-proteasome pathway. This prevents PHLPP-mediated dephosphorylation of AKT, causing sustained AKT activation that promotes growth and inhibits autophagy. SRMS is amplified and overexpressed in human cancers where it drives unrestrained AKT signaling in a kinase-dependent manner. SRMS kinase inhibition activates autophagy, inhibits cancer growth, and can be accomplished using the FDA-approved tyrosine kinase inhibitor ibrutinib. This illuminates SRMS as a targetable vulnerability in human cancers and as a new target for pharmacological induction of autophagy in vertebrates. |
| first_indexed | 2024-12-20T00:56:20Z |
| format | Article |
| id | doaj.art-4164afef6c64473eae9b0a547aaea3fd |
| institution | Directory Open Access Journal |
| issn | 1544-9173 1545-7885 |
| language | English |
| last_indexed | 2024-12-20T00:56:20Z |
| publishDate | 2021-06-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Biology |
| spelling | doaj.art-4164afef6c64473eae9b0a547aaea3fd2022-12-21T19:59:06ZengPublic Library of Science (PLoS)PLoS Biology1544-91731545-78852021-06-01196e300128110.1371/journal.pbio.3001281The nonreceptor tyrosine kinase SRMS inhibits autophagy and promotes tumor growth by phosphorylating the scaffolding protein FKBP51.Jung Mi ParkSeung Wook YangWei ZhuangAsim K BeraYan LiuDeepak GurbaniSergei J von Hoyningen-HueneSadie Miki SakuradaHaiyun GanShondra M Pruett-MillerKenneth D WestoverMalia B PottsNutrient-responsive protein kinases control the balance between anabolic growth and catabolic processes such as autophagy. Aberrant regulation of these kinases is a major cause of human disease. We report here that the vertebrate nonreceptor tyrosine kinase Src-related kinase lacking C-terminal regulatory tyrosine and N-terminal myristylation sites (SRMS) inhibits autophagy and promotes growth in a nutrient-responsive manner. Under nutrient-replete conditions, SRMS phosphorylates the PHLPP scaffold FK506-binding protein 51 (FKBP51), disrupts the FKBP51-PHLPP complex, and promotes FKBP51 degradation through the ubiquitin-proteasome pathway. This prevents PHLPP-mediated dephosphorylation of AKT, causing sustained AKT activation that promotes growth and inhibits autophagy. SRMS is amplified and overexpressed in human cancers where it drives unrestrained AKT signaling in a kinase-dependent manner. SRMS kinase inhibition activates autophagy, inhibits cancer growth, and can be accomplished using the FDA-approved tyrosine kinase inhibitor ibrutinib. This illuminates SRMS as a targetable vulnerability in human cancers and as a new target for pharmacological induction of autophagy in vertebrates.https://doi.org/10.1371/journal.pbio.3001281 |
| spellingShingle | Jung Mi Park Seung Wook Yang Wei Zhuang Asim K Bera Yan Liu Deepak Gurbani Sergei J von Hoyningen-Huene Sadie Miki Sakurada Haiyun Gan Shondra M Pruett-Miller Kenneth D Westover Malia B Potts The nonreceptor tyrosine kinase SRMS inhibits autophagy and promotes tumor growth by phosphorylating the scaffolding protein FKBP51. PLoS Biology |
| title | The nonreceptor tyrosine kinase SRMS inhibits autophagy and promotes tumor growth by phosphorylating the scaffolding protein FKBP51. |
| title_full | The nonreceptor tyrosine kinase SRMS inhibits autophagy and promotes tumor growth by phosphorylating the scaffolding protein FKBP51. |
| title_fullStr | The nonreceptor tyrosine kinase SRMS inhibits autophagy and promotes tumor growth by phosphorylating the scaffolding protein FKBP51. |
| title_full_unstemmed | The nonreceptor tyrosine kinase SRMS inhibits autophagy and promotes tumor growth by phosphorylating the scaffolding protein FKBP51. |
| title_short | The nonreceptor tyrosine kinase SRMS inhibits autophagy and promotes tumor growth by phosphorylating the scaffolding protein FKBP51. |
| title_sort | nonreceptor tyrosine kinase srms inhibits autophagy and promotes tumor growth by phosphorylating the scaffolding protein fkbp51 |
| url | https://doi.org/10.1371/journal.pbio.3001281 |
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