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

• Published in: PLoS biology Vol. 19; no. 6; p. e3001281
• Main Authors: Park, Jung Mi, Yang, Seung Wook, Zhuang, Wei, Bera, Asim K, Liu, Yan, Gurbani, Deepak, von Hoyningen-Huene, Sergei J, Sakurada, Sadie Miki, Gan, Haiyun, Pruett-Miller, Shondra M, Westover, Kenneth D, Potts, Malia B
• Format: Journal Article
• Language: English
• Published: San Francisco Public Library of Science 02.06.2021; Public Library of Science (PLoS)
• Subjects: AKT protein; Autophagy; Autophagy (Cytology); Biology and Life Sciences; Cancer; Care and treatment; Cell death; Cell growth; Dephosphorylation; Enzyme inhibitors; Health aspects; Kinases; Medicine and Health Sciences; Metabolism; Nutrient balance; Phagocytosis; Phosphatase; Phosphorylation; Phosphotransferases; Physical Sciences; Physiological aspects; Prevention; Proteasomes; Protein-tyrosine kinase; Proteins; Regulation; Research and Analysis Methods; Scaffolding; Tacrolimus; Tacrolimus-binding protein; Tumors; Tyrosine; Ubiquitin; Vertebrates; United States
• ISSN: 1545-7885; 1544-9173; 1545-7885
• DOI: 10.1371/journal.pbio.3001281

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.