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

PLoS Biol. 2021 Jun 2;19(6):e3001281. doi: 10.1371/journal.pbio.3001281. eCollection 2021 Jun.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenine / analogs & derivatives
  • Adenine / pharmacology
  • Animals
  • Autophagy* / drug effects
  • Beclin-1 / metabolism
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cellular Senescence / drug effects
  • Enzyme Activation / drug effects
  • Mice
  • Neoplasms / metabolism*
  • Neoplasms / pathology*
  • Nuclear Proteins / metabolism
  • Phosphoprotein Phosphatases / metabolism
  • Phosphorylation / drug effects
  • Phosphotyrosine / metabolism
  • Piperidines / pharmacology
  • Protein Binding / drug effects
  • Proto-Oncogene Proteins c-akt / metabolism
  • Signal Transduction / drug effects
  • Tacrolimus Binding Proteins / metabolism*
  • src-Family Kinases / antagonists & inhibitors
  • src-Family Kinases / metabolism*

Substances

  • Beclin-1
  • Nuclear Proteins
  • Piperidines
  • ibrutinib
  • Phosphotyrosine
  • SRMS protein, human
  • src-Family Kinases
  • Proto-Oncogene Proteins c-akt
  • PHLPP1 protein, human
  • Phosphoprotein Phosphatases
  • Tacrolimus Binding Proteins
  • tacrolimus binding protein 5
  • Adenine