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

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.