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.
Highlights
Ancient nutrient-sensitive kinases such as mTORC1 and AMPK control the metabolic switch between cell growth and adaptive survival [1]
We previously reported that SRMS depletion activates autophagy as evidenced by increased formation of LC3-positive puncta accompanied by the lysosome-dependent degradation of LC3 and p62 in an ULK1- and ATG5-dependent manner [8]
Degradation of the autophagy substrate HiBiT-LC3 was detected as reduced luminescence indicative of increased autophagic flux in SRMS-depleted cells compared to controls
Summary
Ancient nutrient-sensitive kinases such as mTORC1 and AMPK control the metabolic switch between cell growth (when conditions are favorable) and adaptive survival (under times of scarcity) [1]. This is accomplished via opposing regulation of biosynthetic metabolism versus energy-yielding processes such as autophagy [2]. Institutes of Health under Award Number P30 CA021765 (Charles Roberts). The content of this manuscript is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript
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