The intracellular domain of the low density lipoprotein receptor-related protein modulates transactivation mediated by amyloid precursor protein and Fe65

Low density lipoprotein-related protein (LRP) is a transmembrane receptor, localized mainly in hepatocytes, fibroblasts, and neurons. It is implicated in diverse biological processes both as an endocytic receptor and as a signaling molecule. Recent reports show that LRP undergoes sequential proteolytic cleavage in the ectodomain and transmembrane domain. The latter cleavage, mediated by the Alzheimer-related gamma-secretase activity that also cleaves amyloid precursor protein (APP) and Notch, results in the release of the LRP cytoplasmic domain (LRPICD) fragment. This relatively small cytoplasmic fragment has several motifs by which LRP interacts with various intracellular adaptor and scaffold proteins. However, the function of this fragment is largely unknown. Here we show that the LRPICD is translocated to the nucleus, where it colocalizes in the nucleus with a transcription modulator, Tip60, which is known to interact with Fe65 and with the APP-derived intracellular domain. LRPICD dramatically inhibits APP-derived intracellular domain/Fe65 transactivation mediated by Tip60. LRPICD has a close interaction with Tip60 in the nucleus, as shown by a fluorescence resonance energy transfer assay. These observations suggest that LRPICD has a novel signaling function, negatively impacting transcriptional activity of the APP, Fe65, and Tip60 complex in the nucleus, and shed new light on the function of LRP in transcriptional modulation

Using Drosophila models and tools to understand the mechanisms of novel human cancer driver gene function

The formation, overgrowth and metastasis of tumors comprise a complex series of cellular and molecular events resulting from the combined effects of a variety of aberrant signaling pathways, mutations, and epigenetic alterations. Modeling this complexity in vivo requires multiple genes to be manipulated simultaneously, which is technically challenging. Here, we analyze how Drosophila research can further contribute to identifying pathways and elucidating mechanisms underlying novel cancer driver (risk) genes associated with tumor growth and metastasis in humans.Work in the authors laboratory is supported by the Spanish Ministry of Economy and Competitiveness and co-financed by FEDER funds (BFU2015-64239-R, the Spanish State Research Agency, through the “Severo Ochoa” Program for Centers of Excellence in R&D (SEV-2013-0317), the Scientific Foundation of the Spanish Association Against Cancer (AECC) (CICPF16001DOMÍ), and the Valencian Regional Government’s Prometeo Programme for research groups of excellence (PROMETEO/2017/146) to M.D.Peer reviewe