The nonreceptor tyrosine kinase SRMS inhibits autophagy and promotes tumor growth by phosphorylating the scaffolding protein FKBP51

0301 basic medicine QH301-705.5 Tacrolimus Binding Proteins Mice 03 medical and health sciences Piperidines Cell Line, Tumor Neoplasms Autophagy Phosphoprotein Phosphatases Animals Biology (General) Phosphorylation Phosphotyrosine Cellular Senescence Cell Proliferation 0303 health sciences Adenine Nuclear Proteins 3. Good health Enzyme Activation src-Family Kinases Beclin-1 Proto-Oncogene Proteins c-akt Research Article Protein Binding Signal Transduction
DOI: 10.1371/journal.pbio.3001281 Publication Date: 2021-06-03T04:08:40Z
ABSTRACT
Nutrient-responsive protein kinases control the balance between anabolic growth and catabolic processes such as autophagy. Aberrant regulation of these is a major cause human disease. We report here that vertebrate nonreceptor tyrosine kinase Src-related lacking C-terminal regulatory N-terminal myristylation sites (SRMS) inhibits autophagy promotes in nutrient-responsive manner. Under nutrient-replete conditions, SRMS phosphorylates PHLPP scaffold FK506-binding 51 (FKBP51), disrupts FKBP51-PHLPP complex, FKBP51 degradation through ubiquitin-proteasome pathway. This prevents PHLPP-mediated dephosphorylation AKT, causing sustained AKT activation amplified overexpressed cancers where it drives unrestrained signaling kinase-dependent inhibition activates autophagy, cancer growth, can be accomplished using FDA-approved inhibitor ibrutinib. illuminates targetable vulnerability new target for pharmacological induction vertebrates.
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