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

• Main Authors: Jung Mi Park, Seung Wook Yang, Wei Zhuang, Asim K Bera, Yan Liu, Deepak Gurbani, Sergei J von Hoyningen-Huene, Sadie Miki Sakurada, Haiyun Gan, Shondra M Pruett-Miller, Kenneth D Westover, Malia B Potts
• Format: Article
• Language: English
• Published: Public Library of Science (PLoS) 2021-06-01
• Series: PLoS Biology
• Online Access: https://doi.org/10.1371/journal.pbio.3001281
• ISSN: 1544-9173; 1545-7885

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.