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FEBS Lett. 2007 Dec 22;581(30):5814-8. Epub 2007 Nov 29.

Epac signaling pathway involves STEF, a guanine nucleotide exchange factor for Rac, to regulate APP processing.

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Department of Proteomic, CIC bioGUNE, Parque Tecnológico de Bizkaia, Edificio 801A, 48160 Derio, Bizkaia, Spain.


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.

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