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

• DOI: 10.1371/journal.pbio.3001281
• Publication Date: 2021-06-03T04:08:40Z
• Authors: Jung Mi Park; Seung Wook Yang; Wei Zhuang; Asim K. Bera; Yan Liu; Deepak Gurbani; Sergei J. von Hoy...; Sadie Miki Sakurada; Haiyun Gan; Shondra M. Pruett...; Kenneth D. Westover; Malia B. Potts
• Keywords: 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

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.