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 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.
SUPPLEMENTAL MATERIAL
Coming soon ....
REFERENCES (67)
CITATIONS (9)
EXTERNAL LINKS
PlumX Metrics
RECOMMENDATIONS
FAIR ASSESSMENT
Coming soon ....
JUPYTER LAB
Coming soon ....