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Vol. 19, Issue 10, 4201-4212, October 2008

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Tumor Necrosis Factor-–elicited Stimulation of -Secretase Is Mediated by c-Jun N-terminal Kinase-dependent Phosphorylation of Presenilin and Nicastrin

Lan-Hsin Kuo^*,, Ming-Kuan Hu, Wen-Ming Hsu, Ying-Tsen Tung^*,, Bo-Jeng Wang^*, Wang-Wei Tsai^*, Chen-Tung Yen, and Yung-Feng Liao^*,

*Laboratory of Molecular Neurobiology, Institute of Cellular and Organismic Biology, Academia Sinica, Taipei 115, Taiwan; Institute of Zoology, National Taiwan University, Taipei 106, Taiwan; School of Pharmacy, National Defense Medical Center, Taipei 114, Taiwan; and Department of Surgery, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei 100, Taiwan

Submitted October 1, 2007; Revised June 24, 2008; Accepted July 23, 2008
Monitoring Editor: Erika Holzbaur

-Secretase is a multiprotein complex composed of presenilin (PS), nicastrin (NCT), Aph-1, and Pen-2, and it catalyzes the final proteolytic step in the processing of amyloid precursor protein to generate amyloid-β. Our previous results showed that tumor necrosis factor- (TNF-) can potently stimulate -secretase activity through a c-Jun N-terminal kinase (JNK)-dependent pathway. Here, we demonstrate that TNF- triggers JNK-dependent serine/threonine phosphorylation of PS1 and NCT to stimulate -secretase activity. Blocking of JNK activity with a potent JNK inhibitor (SP600125) reduces TNF-–triggered phosphorylation of PS1 and NCT. Consistent with this, we show that activated JNKs can be copurified with -secretase complexes and that active recombinant JNK2 can promote the phosphorylation of PS1 and NCT in vitro. Using site-directed mutagenesis and a synthetic peptide, we clearly show that the Ser³¹⁹Thr³²⁰ motif in PS1 is an important JNK phosphorylation site that is critical for the TNF-–elicited regulation of -secretase. This JNK phosphorylation of PS1 at Ser³¹⁹Thr³²⁰ enhances the stability of the PS1 C-terminal fragment that is necessary for -secretase activity. Together, our findings strongly suggest that JNK is a critical intracellular mediator of TNF-–elicited regulation of -secretase and governs the pivotal step in the assembly of functional -secretase.

Address correspondence to: Yung-Feng Liao (yliao{at}sinica.edu.tw)

Abbreviations used: Aβ, amyloid-β; AD, Alzheimer's disease; AICD, amyloid precursor protein intracellular domain; APP, amyloid precursor protein; C99-CTF, 99-residue C-terminal fragment of APP; DAPT, N-[N-(3,5-difluorophenacetyl-L-alanyl)]-S-phenylglycine t-butyl ester; ELISA, enzyme-linked immunosorbent assay; JNK, c-Jun N-terminal kinase; MAP kinase, mitogen-activated protein kinase; NICD, Notch intracellular domain; PS, presenilin; TNF-, tumor necrosis factor-.