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
AUTHORS (12)
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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CITATIONS (9)
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