The nonreceptor tyrosine kinase SRMS inhibits autophagy and promotes tumor growth by phosphorylating the scaffolding protein FKBP51.
| Title: | The nonreceptor tyrosine kinase SRMS inhibits autophagy and promotes tumor growth by phosphorylating the scaffolding protein FKBP51. |
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| Authors: | 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 |
| Source: | PLoS Biology, Vol 19, Iss 6, p e3001281 (2021) |
| Publisher Information: | Public Library of Science (PLoS), 2021. |
| Publication Year: | 2021 |
| Collection: | LCC:Biology (General) |
| Subject Terms: | Biology (General), QH301-705.5 |
| More Details: | 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. |
| Document Type: | article |
| File Description: | electronic resource |
| Language: | English |
| ISSN: | 1544-9173 1545-7885 |
| Relation: | https://doaj.org/toc/1544-9173; https://doaj.org/toc/1545-7885 |
| DOI: | 10.1371/journal.pbio.3001281 |
| Access URL: | https://doaj.org/article/4164afef6c64473eae9b0a547aaea3fd |
| Accession Number: | edsdoj.4164afef6c64473eae9b0a547aaea3fd |
| Database: | Directory of Open Access Journals |
| ISSN: | 15449173 15457885 |
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| DOI: | 10.1371/journal.pbio.3001281 |
| Published in: | PLoS Biology |
| Language: | English |