. A {gamma}-secretase-independent mechanism of signal transduction by the amyloid precursor protein. J Biol Chem. 2005 Nov 4;280(44):36895-904. PubMed.


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  1. Amyloid precursor protein (APP), a γ-secretase substrate, was thought to have a nuclear function in regulating Tip60-mediated transcription. In this paper, the authors unequivocally demonstrate that APP proteolysis, and therefore nuclear translocation, has little to do with its role in activating Tip60 histone acetyltransferase. APP can do so in cells lacking presenilin 1 and 2, which are therefore deficient in γ-secretase. The alternative mechanism they find is that CDK-mediated phosphorylation activates Tip60, and APP, through Fe65, permits Tip60 and CDK association. Proteolysis of APP may in fact terminate this event. Nuclear functions assigned to APP will have to be re-examined with similar controls. This fits well with our prediction that γ-secretase will have three functions: 1. the "proteasome" of the membrane, that is, degradation function; 2. regulating ON rate (Notch, ErbB4) and 3. regulating OFF rate (DCC, APP) (Kopan and Ilagan, 2004).


    . Gamma-secretase: proteasome of the membrane?. Nat Rev Mol Cell Biol. 2004 Jun;5(6):499-504. PubMed.

  2. Tip60 is a histone acetyltransferase implicated in transcriptional activation and DNA repair. The intracellular domain generated from membranous cleavage of APP by γ-secretase is suggested to lead to activation of the transcriptional activity of Tip60 in a Fe65-dependent manner. In this study, Matt Hass and Bruce Yankner provide evidence for a γ-secretase independent mechanism of activation of Tip60 (Hass and Yankner, 2005). Activation of Tip60 transcription by APP and Fe65 is observed in PS1/PS2 double-deficient cells, and in cells treated with γ-secretase inhibitors. Furthermore, Tip60 associates with holo-APP in the presence of Fe65. In contrast to the conventional paradigm, these findings suggest that membrane-anchored holo-APP regulates Fe65/Tip60 transcriptional activity from afar through sequestration to membrane compartments.

    Interestingly, the authors suggest that an important consequence of membrane sequestration is phosphorylation of Tip60 by colocalized CDKs. Two potential CDK phosphorylation sites on Tip60 were identified, and it was shown that the APP-dependent activation of transcriptional activity of Tip60 is abolished in the absence of CDK phosphorylation. The authors suggest that CDK phosphorylation of Tip60 and APP helps stabilize Tip60 protein and induces dissociation of Tip60/Fe65 from the membrane, respectively.

    • This study reveals an unexpected function of holo-APP in transcriptional regulation, and an unexpected role for membrane-bound CDKs, such as CDK5, in this process. As deregulation of CDK5 is implicated in Alzheimer disease (Cruz and Tsai, 2004; Patrick et al., 1999), it is an intriguing possibility that hyperphosphorylation of Tip60 by CDK5 may contribute to this process. As gain-of-function and loss-of-function CDK5 mouse models are readily available (Chae et al., 1997; Cruz et al., 2003; Ohshima et al., 1996), it would be interesting to determine the localization and transcriptional activity of Tip60 in brains of these animals.


    . A {gamma}-secretase-independent mechanism of signal transduction by the amyloid precursor protein. J Biol Chem. 2005 Nov 4;280(44):36895-904. PubMed.

    . Conversion of p35 to p25 deregulates Cdk5 activity and promotes neurodegeneration. Nature. 1999 Dec 9;402(6762):615-22. PubMed.

    . Mice lacking p35, a neuronal specific activator of Cdk5, display cortical lamination defects, seizures, and adult lethality. Neuron. 1997 Jan;18(1):29-42. PubMed.

    . Aberrant Cdk5 activation by p25 triggers pathological events leading to neurodegeneration and neurofibrillary tangles. Neuron. 2003 Oct 30;40(3):471-83. PubMed.

    . Targeted disruption of the cyclin-dependent kinase 5 gene results in abnormal corticogenesis, neuronal pathology and perinatal death. Proc Natl Acad Sci U S A. 1996 Oct 1;93(20):11173-8. PubMed.

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