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 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.
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