mTOR independent alteration in ULK1 Ser758 phosphorylation following chronic LRRK2 kinase inhibition

Biosci Rep. 2018 Apr 20;38(2):BSR20171669. doi: 10.1042/BSR20171669. Print 2018 Apr 26.

Abstract

Unc-51 Like Kinase 1 (ULK1) is a critical regulator of the biogenesis of autophagosomes, the central component of the catabolic macroautophagy pathway. Regulation of ULK1 activity is dependent upon several phosphorylation events acting to repress or activate the enzymatic function of this protein. Phosphorylation of Ser758 ULK1 has been linked to repression of autophagosome biogenesis and was thought to be exclusively dependent upon mTOR complex 1 kinase activity. In the present study, a novel regulation of Ser758 ULK1 phosphorylation is reported following prolonged inhibition of the Parkinson's disease linked protein leucine rich repeat kinase 2 (LRRK2). Here, modulation of Ser758 ULK1 phosphorylation following LRRK2 inhibition is decoupled from the repression of autophagosome biogenesis and independent of mTOR complex 1 activity.

Keywords: Leucin Rich Repeat Kinase 2 (LRRK2); Parkinson disease; Unc-51 Like Kinase 1 (ULK1); autophagy; cancer; mammalian Target Of Rapamycin (mTOR).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autophagosomes / enzymology*
  • Autophagy-Related Protein-1 Homolog / genetics
  • Autophagy-Related Protein-1 Homolog / metabolism*
  • Cell Line
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 / antagonists & inhibitors*
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 / genetics
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 / metabolism
  • Mechanistic Target of Rapamycin Complex 1 / genetics
  • Mechanistic Target of Rapamycin Complex 1 / metabolism
  • Phosphorylation / genetics
  • Rats
  • Serine / genetics
  • Serine / metabolism
  • TOR Serine-Threonine Kinases / genetics
  • TOR Serine-Threonine Kinases / metabolism*

Substances

  • Serine
  • mTOR protein, rat
  • Autophagy-Related Protein-1 Homolog
  • LRRK2 protein, rat
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
  • Mechanistic Target of Rapamycin Complex 1
  • TOR Serine-Threonine Kinases
  • ULK1 protein, rat