PLoS Biology (Jun 2021)

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

  • 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

DOI
https://doi.org/10.1371/journal.pbio.3001281
Journal volume & issue
Vol. 19, no. 6
p. e3001281

Abstract

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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.