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.
Zaldua
Natalia
N
Department of Proteomic, CIC bioGUNE, Parque Tecnológico de Bizkaia, Edificio 801A, 48160 Derio, Bizkaia, Spain.
Gastineau
Monique
M
Hoshino
Mikio
M
Lezoualc'h
Frank
F
Zugaza
José L
JL
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