Yang Z, Cool BH, Martin GM, Hu Q.
A dominant role for FE65 (APBB1) in nuclear signaling.
J Biol Chem. 2006 Feb 17;281(7):4207-14.
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This paper confirms the possible role of Fe65 in the regulation of transcription. I think that all the results currently available are insufficient to exclude (or minimize) the role of APP (or AICD) in the nuclear functions of Fe65.
First, intracellular trafficking of Fe65 is dependent on APP (and APLP1-APLP2), as intact APP-APLPs are strong extranuclear anchor sites for Fe65. Thus, nuclear availability of Fe65 could be regulated by several events, such as the phosphorylation at T668 of APP (1) or its proteolytic cleavage and intracellular localization, or by the competition with other ligands of the APP cytodomain.
Second, there is experimental evidence that the interaction of Fe65 with APP (and likely with APLPs) is needed to render Fe65 “competent” to carry out its nuclear function(s). In fact, this interaction could be responsible for a conformational change of Fe65 (2) and/or could favor its phosphorylation (3) and/or the interaction with other relevant molecules. It is worth noting, for example, that the overexpression of both APP and Fe65, but not of Fe65 alone, is necessary to detect a chromatin-associated complex on the KAI1 gene promoter (4). Third, ChIP experiments demonstrated that antibodies directed against the C-terminal domain of APP are able to immunoprecipitate chromatinized complexes (4,5) and numerous results support the existence of a nuclear fraction of AICD (6-10), often associated with subnuclear structures.
I recommend this paper. There is only one discrepancy with our results: Both Fe65L1 and L2 are translocated into the nucleus (11).
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