Negative regulation of Vps34 by Cdk mediated phosphorylation.

نویسندگان

  • Tsuyoshi Furuya
  • Minsu Kim
  • Marta Lipinski
  • Juying Li
  • Dohoon Kim
  • Tao Lu
  • Yong Shen
  • Lucia Rameh
  • Bruce Yankner
  • Li-Huei Tsai
  • Junying Yuan
چکیده

Vacuolar protein sorting 34 (Vps34) complexes, the class III PtdIns3 kinase, specifically phosphorylate the D3 position of PtdIns to produce PtdIns3P. Vps34 is involved in the control of multiple key intracellular membrane trafficking pathways including endocytic sorting and autophagy. In mammalian cells, Vps34 interacts with Beclin 1, an ortholog of Atg6 in yeast, to regulate the production of PtdIns3P and autophagy. We show that Vps34 is phosphorylated on Thr159 by Cdk1, which negatively regulates its interaction with Beclin 1 during mitosis. Cdk5/p25, a neuronal Cdk shown to play a role in Alzheimer's disease, can also phosphorylate Thr159 of Vps34. Phosphorylation of Vps34 on Thr159 inhibits its interaction with Beclin 1. We propose that phosphorylation of Thr159 in Vps34 is a key regulatory mechanism that controls the class III PtdIns3 kinase activity in cell-cycle progression, development, and human diseases including neurodegeneration and cancers.

برای دانلود متن کامل این مقاله و بیش از 32 میلیون مقاله دیگر ابتدا ثبت نام کنید

ثبت نام

اگر عضو سایت هستید لطفا وارد حساب کاربری خود شوید

منابع مشابه

FBXL20-mediated Vps34 ubiquitination as a p53 controlled checkpoint in regulating autophagy and receptor degradation.

Vacuolar protein-sorting 34 (Vps34), the catalytic subunit in the class III PtdIns3 (phosphatidylinositol 3) kinase complexes, mediates the production of PtdIns3P, a key intracellular lipid involved in regulating autophagy and receptor degradation. However, the signal transduction pathways by which extracellular signals regulate Vps34 complexes and the downstream cellular mechanisms are not wel...

متن کامل

pp60c-Src phosphorylates and activates vacuolar protein sorting 34 to mediate cellular transformation.

Vacuolar protein sorting 34 (VPS34) contributes to the regulation of the mammalian target of rapamycin complex 1/S6 kinase 1 pathway downstream of nutrient signaling. However, intracellular mechanisms leading to VPS34 activation remain unclear. Here, we report that Src directly phosphorylates VPS34, and that this phosphorylation activates VPS34 lipid kinase activity, leading to Src-Y527F-mediat...

متن کامل

Differential Regulation of Distinct Vps34 Complexes by AMPK in Nutrient Stress and Autophagy

Autophagy is a stress response protecting cells from unfavorable conditions, such as nutrient starvation. The class III phosphatidylinositol-3 kinase, Vps34, forms multiple complexes and regulates both intracellular vesicle trafficking and autophagy induction. Here, we show that AMPK plays a key role in regulating different Vps34 complexes. AMPK inhibits the nonautophagy Vps34 complex by phosph...

متن کامل

mTOR activates the VPS34–UVRAG complex to regulate autolysosomal tubulation and cell survival

Lysosomes are essential organelles that function to degrade and recycle unwanted, damaged and toxic biological components. Lysosomes also act as signalling platforms in activating the nutrient-sensing kinase mTOR. mTOR regulates cellular growth, but it also helps to maintain lysosome identity by initiating lysosomal tubulation through a process termed autophagosome-lysosome reformation (ALR). H...

متن کامل

Mouse skeletal muscle fiber-type-specific macroautophagy and muscle wasting are regulated by a Fyn/STAT3/Vps34 signaling pathway.

Skeletal muscle atrophy induced by aging (sarcopenia), inactivity, and prolonged fasting states (starvation) is predominantly restricted to glycolytic type II muscle fibers and typical spares oxidative type I fibers. However, the mechanisms accounting for muscle fiber-type specificity of atrophy have remained enigmatic. In the current study, although the Fyn tyrosine kinase activated the mTORC1...

متن کامل

ذخیره در منابع من


  با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید

برای دانلود متن کامل این مقاله و بیش از 32 میلیون مقاله دیگر ابتدا ثبت نام کنید

ثبت نام

اگر عضو سایت هستید لطفا وارد حساب کاربری خود شوید

عنوان ژورنال:
  • Molecular cell

دوره 38 4  شماره 

صفحات  -

تاریخ انتشار 2010