Fyn modulation of Dab1 effects on amyloid precursor protein and ApoE receptor 2 processing.
Dab1 is an intracellular adaptor protein that interacts with amyloid precursor protein (APP) and apoE receptor 2 (apoEr2), increases their levels on the cell surface, and increases their cleavage by alpha-secretases. To investigate the mechanism underlying these alterations in processing and trafficking of APP and apoEr2, we examined the effect of Fyn, an Src family-tyrosine kinase known to interact with and phosphorylate Dab1. Co-immunoprecipitation, co-immunostaining, and fluorescence lifetime imaging demonstrated an association between Fyn and APP. Fyn induced phosphorylation of APP at Tyr-757 of the (757)YENPTY(762) motif and increased cell surface expression of APP. Overexpression of Fyn alone did not alter levels of sAPPalpha or cytoplasmic C-terminal fragments, although it significantly decreased production of Abeta. However, in the presence of Dab1, Fyn significantly increased sAPPalpha and C-terminal fragments. Fyn-induced APP phosphorylation and cell surface levels of APP were potentiated in the presence of Dab1. Fyn also induced phosphorylation of apoEr2 and increased its cell surface levels and, in the presence of Dab1, affected processing of its C-terminal fragment. In vivo studies showed that sAPPalpha was decreased in the Fyn knock-out, supporting a role for Fyn in APP processing. These data demonstrate that Fyn, due in part to its effects on Dab1, regulates the phosphorylation, trafficking, and processing of APP and apoEr2.
Hoe
Hyang-Sook
HS
Department of Neuroscience, Georgetown University Medical Center, 3970 Reservoir Road NW, Washington, DC 20057, USA.
Minami
S Sakura
SS
Makarova
Alexandra
A
Lee
Jiyeon
J
Hyman
Bradley T
BT
Matsuoka
Yasuji
Y
Rebeck
G William
GW
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D020816:Amino Acid Motifs; D053829:Amyloid Precursor Protein Secretases / Q000235:genetics / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D006801:Humans; D026502:LDL-Receptor Related Proteins; D026503:Low Density Lipoprotein Receptor-Related Protein-1 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational / Q000502:physiology; D021381:Protein Transport / Q000502:physiology; D051076:Proto-Oncogene Proteins c-fyn / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018110:Receptors, Lipoprotein / Q000235:genetics / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; D016564:Amyloid beta-Protein Precursor; C115785:DAB1 protein, human; C103773:Dab1 protein, mouse; C499786:Dab1 protein, rat; D026502:LDL-Receptor Related Proteins; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D009419:Nerve Tissue Proteins; D018110:Receptors, Lipoprotein; C098773:low density lipoprotein receptor-related protein 8; C494957:FYN protein, human; C494960:Fyn protein, mouse; C494961:Fyn protein, rat; D051076:Proto-Oncogene Proteins c-fyn; D053829:Amyloid Precursor Protein Secretases