Biologically active domain of the secreted form of the amyloid beta/A4 protein precursor.
The amyloid beta/A4 protein precursor (APP), a large transmembrane protein, is expressed ubiquitously in many organisms, as well as in a variety of cultured cells. Studies of the synthesis and processing of APP have revealed several intricate metabolic pathways for this protein. One of these pathways involves the cleavage of APP in the middle of the beta/A4 domain and results in the secretion of the large amino-terminal portion of the protein. The biological function of this secreted form of APP has been the subject of intense investigation by several groups and various activities have been described for the different domains of APP studied. Our initial approach was to create a fibroblast cell line in which APP expression is dramatically reduced. These fibroblasts, called A-1, have a very slow growth rate. Addition of exogenous APP in the medium of A-1 cells restores their growth to the level of normal parent fibroblasts, demonstrating a growth factor-like activity for the secreted form of APP. Using APP fragments made in bacteria as well as synthetic peptides, we have been able to locate the active site of APP within a domain of 17 amino-acids (Ala319-Met335). This domain of APP can stimulate neurite extension of cultured neuroblastoma cells and it is proposed that APP mediates this effect through binding to a cell surface receptor, triggering intracellular transduction mechanisms. Thus, the secreted form of APP can function as a growth and/or differentiation factor and the site involved in these activities is within a 17-mer domain in the middle of the molecule. Our current lines of research seek to further characterize the mechanisms of APP function as well as its activity in vivo.
Roch
J M
JM
Department of Neurosciences, University of California San Diego, La Jolla.
Jin
L W
LW
Ninomiya
H
H
Schubert
D
D
Saitoh
T
T
D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000096:biosynthesis* / Q000502:physiology; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000378:metabolism; D002460:Cell Line; D006801:Humans; D008969:Molecular Sequence Data; D014407:Tumor Cells, Cultured
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor