Epac signaling pathway involves STEF, a guanine nucleotide exchange factor for Rac, to regulate APP processing.
The amyloid precursor protein (APP) is a key protein involved in the development of Alzheimer's disease. We previously identified a signal transduction secretory pathway in which the small G protein Rac sets downstream of the cAMP/Epac/Rap1 signalling cascade regulating the alpha cleavage of APP [Maillet, M. et al. (2003) Crosstalk between Rap and Rac regulates secretion of sAPP alpha. Nat. Cell Biol. 5, 633-639]. We now report that Rap1 can physically and specifically associate with the guanine nucleotide exchange factor (GEF) STEF through its TSS region. A deleted TSS domain of STEF cells fails to activate Rac1 and dramatically decreases secretion of the non-amyloidogenic soluble form of APP (sAPP alpha) induced by the cAMP-binding protein Epac. Altogether, our data show that upon Epac activation, Rap1 recruits STEF through its TSS region and activates Rac1, which mediates APP processing.
Department of Proteomic, CIC bioGUNE, Parque Tecnológico de Bizkaia, Edificio 801A, 48160 Derio, Bizkaia, Spain.
Natalia
N
Zaldua
Monique
M
Gastineau
Mikio
M
Hoshino
Frank
F
Lezoualc'h
José L
JL
Zugaza
D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D016466:CHO Cells; D019556:COS Cells; D002522:Chlorocebus aethiops; D006224:Cricetinae; D003412:Cricetulus; D004789:Enzyme Activation; D020662:Guanine Nucleotide Exchange Factors / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D011499:Protein Processing, Post-Translational; D017434:Protein Structure, Tertiary; D044422:Receptors, Serotonin, 5-HT4 / Q000378:metabolism; D015398:Signal Transduction; D012995:Solubility; D020744:rac GTP-Binding Proteins / Q000378:metabolism*; D020827:rap1 GTP-Binding Proteins / Q000378:metabolism
D016229:Amyloid beta-Peptides; D020662:Guanine Nucleotide Exchange Factors; D044422:Receptors, Serotonin, 5-HT4; D020744:rac GTP-Binding Proteins; D020827:rap1 GTP-Binding Proteins