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).
Ando K, Iijima KI, Elliott JI, Kirino Y, Suzuki T.
Phosphorylation-dependent regulation of the interaction of amyloid precursor protein with Fe65 affects the production of beta-amyloid.
J Biol Chem. 2001 Oct 26;276(43):40353-61.
Cao X, Südhof TC.
Dissection of amyloid-beta precursor protein-dependent transcriptional transactivation.
J Biol Chem. 2004 Jun 4;279(23):24601-11.
Perkinton MS, Standen CL, Lau KF, Kesavapany S, Byers HL, Ward M, McLoughlin DM, Miller CC.
The c-Abl tyrosine kinase phosphorylates the Fe65 adaptor protein to stimulate Fe65/amyloid precursor protein nuclear signaling.
J Biol Chem. 2004 May 21;279(21):22084-91.
Telese F, Bruni P, Donizetti A, Gianni D, D'Ambrosio C, Scaloni A, Zambrano N, Rosenfeld MG, Russo T.
Transcription regulation by the adaptor protein Fe65 and the nucleosome assembly factor SET.
EMBO Rep. 2005 Jan;6(1):77-82.
Baek SH, Ohgi KA, Rose DW, Koo EH, Glass CK, Rosenfeld MG.
Exchange of N-CoR corepressor and Tip60 coactivator complexes links gene expression by NF-kappaB and beta-amyloid precursor protein.
Cell. 2002 Jul 12;110(1):55-67.
von Rotz RC, Kohli BM, Bosset J, Meier M, Suzuki T, Nitsch RM, Konietzko U.
The APP intracellular domain forms nuclear multiprotein complexes and regulates the transcription of its own precursor.
J Cell Sci. 2004 Sep 1;117(Pt 19):4435-48.
Kimberly WT, Zheng JB, Guénette SY, Selkoe DJ.
The intracellular domain of the beta-amyloid precursor protein is stabilized by Fe65 and translocates to the nucleus in a notch-like manner.
J Biol Chem. 2001 Oct 26;276(43):40288-92.
Muresan Z, Muresan V.
A phosphorylated, carboxy-terminal fragment of beta-amyloid precursor protein localizes to the splicing factor compartment.
Hum Mol Genet. 2004 Mar 1;13(5):475-88.
Kinoshita A, Whelan CM, Smith CJ, Berezovska O, Hyman BT.
Direct visualization of the gamma secretase-generated carboxyl-terminal domain of the amyloid precursor protein: association with Fe65 and translocation to the nucleus.
J Neurochem. 2002 Aug;82(4):839-47.
Gao Y, Pimplikar SW.
The gamma -secretase-cleaved C-terminal fragment of amyloid precursor protein mediates signaling to the nucleus.
Proc Natl Acad Sci U S A. 2001 Dec 18;98(26):14979-84.
Bruni P, Minopoli G, Brancaccio T, Napolitano M, Faraonio R, Zambrano N, Hansen U, Russo T.
Fe65, a ligand of the Alzheimer's beta-amyloid precursor protein, blocks cell cycle progression by down-regulating thymidylate synthase expression.
J Biol Chem. 2002 Sep 20;277(38):35481-8. Epub 2002 Jun 27