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 is a major cause human disease. We report here that vertebrate nonreceptor tyrosine kinase Src-related lacking C-terminal regulatory N-terminal myristylation sites (SRMS) inhibits autophagy promotes in nutrient-responsive manner. Under nutrient-replete conditions, SRMS phosphorylates PHLPP scaffold FK506-binding 51 (FKBP51), disrupts FKBP51-PHLPP complex, FKBP51 degradation through ubiquitin-proteasome pathway. This prevents PHLPP-mediated dephosphorylation AKT, causing sustained AKT activation amplified overexpressed cancers where it drives unrestrained signaling kinase-dependent inhibition activates autophagy, cancer growth, can be accomplished using FDA-approved inhibitor ibrutinib. illuminates targetable vulnerability new target for pharmacological induction vertebrates.