Low-density lipoprotein receptor-related protein levels and endocytic function are reduced by overexpression of the FE65 adaptor protein, FE65L1.
The FE65 adaptor protein family was identified in two-hybrid screens as proteins that bind the cytoplasmic domain of the amyloid precursor protein (APP). Studies have shown that FE65 binding to APP modulates APP processing. Increased levels of alpha-secretase derived secreted APP (APPsalpha) and beta-amyloid (Abeta) were recovered from conditioned media upon FE65L1 or FE65 overexpression. These effects were associated with an increase in the ratio of mature/immature APP and increased cell-surface APP. FE65 has also been reported to bind low-density lipoprotein receptor-related protein (LRP). Here we show that FE65L1 overexpression results in decreased LRP steady state levels, LRPs, and LRP endocytic receptor function. These changes in LRP protein levels are not due to decreased transcription of LRP. Furthermore, pulse/chase experiments demonstrate that changes in LRP protein only occurred 12-18 h after translation. We conclude that the decreases in LRP levels likely reflect routing of LRP away from the cell surface into a degradative pathway. Previous studies suggested that LRP plays an important role for Abeta production of Kunitz protease inhibitor forms of APP in the endocytic pathway. These data show that FE65L1 can differentially affect the metabolic fate of APP and LRP. In addition, these data suggest that the LRP decrease observed in FE65L1 overexpressing cells may in part contribute to altered APP processing.
D048868:Adaptor Proteins, Signal Transducing; D015152:Blotting, Northern; D015153:Blotting, Western; D002352:Carrier Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000494:pharmacology; D002462:Cell Membrane / Q000378:metabolism; D004705:Endocytosis / Q000187:drug effects / Q000502:physiology*; D015870:Gene Expression; D005910:Glioma / Q000378:metabolism; D006801:Humans; D026503:Low Density Lipoprotein Receptor-Related Protein-1 / Q000235:genetics / Q000378:metabolism*; D011233:Precipitin Tests; D012333:RNA, Messenger / Q000378:metabolism; D014162:Transfection; D014407:Tumor Cells, Cultured
C466684:APBB2 protein, human; D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D012333:RNA, Messenger