. APP is phosphorylated by TrkA and regulates NGF/TrkA signaling. J Neurosci. 2011 Aug 17;31(33):11756-61. PubMed.


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  1. This study by Matrone et al. establishes a reciprocal, functional link between the post-translational modification of the amyloid-β precursor protein (APP) and the NGF/TrkA signaling pathway that could be relevant to Alzheimer’s disease (AD). This article is also important for at least two other reasons. First, together with other papers from D’Adamio’s lab (1-10), it draws attention to the relevance of APP phosphorylation for the normal function of APP and pathogenesis of AD.

    APP is phosphorylated at multiple sites within its intracellular domain; the phosphorylating kinases, and the mechanisms of phosphorylation, are just beginning to be elucidated (5,7,11-13).

    In addition, the article tacitly touches the controversy of whether APP is—or is not—a key regulator of intraneuronal transport processes (14). The paper does not directly address the possibility that APP regulates NGF/TrkA signaling through the regulation of transport of signaling proteins, nor does it address whether the changes in processing of APP via neurotrophic signaling involves altered trafficking of APP. Nevertheless, the findings that APP and TrkA do interact, and regulate each other’s subcellular distribution, as this paper shows, certainly point towards such mechanisms. We also note that APP, its processing machinery, and TrkA have been previously tied together in a common transport pathway (15). Thus, it becomes clear that alterations in intracellular trafficking could be part of AD pathogenesis. Of course, the dilemma is whether the abnormal transport causes the alterations in APP post-translational modifications (including enhancement of its amyloidogenic processing), or whether the altered function of APP leads to abnormal transport.


    . The intracellular threonine of amyloid precursor protein that is essential for docking of Pin1 is dispensable for developmental function. PLoS One. 2011;6(3):e18006. PubMed.

    . Tyr(682) in the intracellular domain of APP regulates amyloidogenic APP processing in vivo. PLoS One. 2010;5(11):e15503. PubMed.

    . Hyperphosphorylation of JNK-interacting protein 1, a protein associated with Alzheimer disease. Mol Cell Proteomics. 2006 Jan;5(1):97-113. PubMed.

    . Transgenic expression of the amyloid-beta precursor protein-intracellular domain does not induce Alzheimer's Disease-like traits in vivo. PLoS One. 2010;5(7):e11609. PubMed.

    . Amyloid beta protein precursor is phosphorylated by JNK-1 independent of, yet facilitated by, JNK-interacting protein (JIP)-1. J Biol Chem. 2003 Oct 24;278(43):42058-63. PubMed.

    . The interactome of the amyloid beta precursor protein family members is shaped by phosphorylation of their intracellular domains. Mol Neurodegener. 2009;4:28. PubMed.

    . Evidence for a role of the nerve growth factor receptor TrkA in tyrosine phosphorylation and processing of beta-APP. Biochem Biophys Res Commun. 2002 Jul 12;295(2):324-9. PubMed.

    . Tyrosine phosphorylation of the beta-amyloid precursor protein cytoplasmic tail promotes interaction with Shc. J Biol Chem. 2002 May 10;277(19):16798-804. PubMed.

    . Growth factor receptor-bound protein 2 interaction with the tyrosine-phosphorylated tail of amyloid beta precursor protein is mediated by its Src homology 2 domain. J Biol Chem. 2004 Jun 11;279(24):25374-80. PubMed.

    . Phosphorylation of a tyrosine in the amyloid-beta protein precursor intracellular domain inhibits Fe65 binding and signaling. J Alzheimers Dis. 2009;16(2):301-7. PubMed.

    . APP processing is regulated by cytoplasmic phosphorylation. J Cell Biol. 2003 Oct 13;163(1):83-95. PubMed.

    . c-Jun NH2-terminal kinase-interacting protein-3 facilitates phosphorylation and controls localization of amyloid-beta precursor protein. J Neurosci. 2005 Apr 13;25(15):3741-51. PubMed.

    . The amyloid-beta precursor protein is phosphorylated via distinct pathways during differentiation, mitosis, stress, and degeneration. Mol Biol Cell. 2007 Oct;18(10):3835-44. PubMed.

    . Is abnormal axonal transport a cause, a contributing factor or a consequence of the neuronal pathology in Alzheimer's disease?. Future Neurol. 2009 Nov 1;4(6):761-773. PubMed.

    . Kinesin-mediated axonal transport of a membrane compartment containing beta-secretase and presenilin-1 requires APP. Nature. 2001 Dec 6;414(6864):643-8. PubMed.

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