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

Abstract

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 a cleavage of APP [Maillet, M. et al. (2003) Crosstalk between Rap and Rac regulates secretion of sAPPa. 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 nonamyloidogenic soluble form of APP (sAPPa) 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.

The Epac-Rap1 Signaling Pathway Controls cAMP-mediated Exocytosis of Weibel-Palade Bodies in Endothelial Cells

“…Rac1 has also been identified as a downstream effector of Epac/Rap1 in the release of amyloid precursor protein from transfected CHO cells (49). Subsequent studies revealed that Rap1 interacts with the Rac1-specific guanine exchange factor STEF in this system (50). Interestingly, Rac1 has been implicated in release of WPBs (51).…”

Guanine Nucleotide Exchange Factor αPIX Leads to Activation of the Rac 1 GTPase/Glycogen Phosphorylase Pathway in Interleukin (IL)-2-stimulated T Cells

“…Although, additional GEFs from the Dbl family of exchange factors such as Tiam-1 and STEF are capable of activating Rac 1 (28,54), these GEFs have not been reported as being activated by tyrosine phosphorylation, but rather Tiam-1 was reported being activated by threonine phosphorylation (30), whereas STEF was reported being activated by serine/threonine phosphorylation (31). Even so, their effects on PYGM activity were evaluated.…”

Epac activation initiates associative odor preference memories in the rat pup

“…In contrast, another recent study reported Epac activation in the nucleus accumbens interfered with conditioned place preference learning (Park et al 2014). In broader learning and memory contexts, changes in Epac regulation have been implicated in the underpinnings of Alzheimer's disease (McPhee et al 2005;Zaldua et al 2007;Grandoch et al 2010), schizophrenia (Kelly et al 2009), and autism (Srivastava et al 2012).…”