Phospho-dependent ubiquitination and degradation of PAR-1 regulates synaptic morphology and tau-mediated Aβ toxicity in Drosophila

Seongsoo Lee, Ji Wu Wang, Wendou Yu, Bingwei Lu

Research output: Contribution to journalArticle

32 Citations (Scopus)

Abstract

The conserved kinases PAR-1/MARK are critically involved in processes such as asymmetric cell division, cell polarity and neuronal differentiation. Their deregulation has been implicated in diseases including Alzheimer's disease and cancer. Given the importance of PAR-1/MARK in health and disease, their activities need to be tightly controlled. However, little is known about the molecular mechanisms underlying their regulation in vivo. Here we show that in Drosophila, a phosphorylation-dependent ubiquitination mechanism restrains PAR-1 activation. Active PAR-1 generated by LKB1-controlled phosphorylation is targeted for ubiquitination and degradation by SCF (Skp, Cullin, F-box containing complex) (Slimb), whose action is antagonized by the deubiquitinating enzyme fat facets. This newly identified PAR-1-modifying module critically regulates synaptic morphology and tau-mediated postsynaptic toxicity of amyloid precursor protein (APP)/Aβ-42, the causative agents of Alzheimer's disease, at the Drosophila neuromuscular junction. Our results provide new insights into the regulation of PAR-1 in various physiological processes and offer new therapeutic strategies for diseases involving PAR-1/MARK deregulation.

Original languageEnglish (US)
Article number2278
JournalNature Communications
Volume3
DOIs
StatePublished - 2012
Externally publishedYes

Fingerprint

Drosophila
Ubiquitination
toxicity
Toxicity
Serum Amyloid A Protein
degradation
Degradation
Alzheimer Disease
phosphorylation
Cullin Proteins
Phosphorylation
Asymmetric Cell Division
Deregulation
Physiological Phenomena
Cell Polarity
Amyloid beta-Protein Precursor
Neuromuscular Junction
cell division
Phosphotransferases
Fats

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Chemistry(all)
  • Physics and Astronomy(all)

Cite this

Phospho-dependent ubiquitination and degradation of PAR-1 regulates synaptic morphology and tau-mediated Aβ toxicity in Drosophila. / Lee, Seongsoo; Wang, Ji Wu; Yu, Wendou; Lu, Bingwei.

In: Nature Communications, Vol. 3, 2278, 2012.

Research output: Contribution to journalArticle

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