Editors' ChoiceREGULATED SECRETION

Rac and Rap1 Regulate Soluble Amyloid Precursor Protein Secretion

STKE  08 Jul 2003:
Vol. 2003, Issue 190, pp. tw262-TW262
DOI: 10.1126/stke.2003.190.tw262

Maillet et al. determined that regulation of secretion of nonamyloidogenic soluble amyloid precursor protein (sAPPα) was mediated by a novel signal transduction pathway involving crosstalk between the Ras and Rho families of small guanosine triphosphatases (GTPases). Activation of the Gs-coupled serotonin (5-HT4) receptor stimulated sAPPα release in Chinese hamster ovary (CHO) cells transfected to express both human 5-HT4 receptors and a human APP and in primary cultures of mouse cortical neurons. [Gs are the family of heterotrimeric guanine nucleotide-binding protein (G protein) α subunits thatstimulate adenylyl cyclase.] Pharmacologic analysis indicated that 5-HT4-mediated sAPPα secretion involved cyclic adenosine 3′,5′-monophosphate (cAMP), but was independent of protein kinase A (PKA). Similarly, 5-HT4-mediated activation of the Rho GTPase Rac (assessed by the fraction of GTP-bound Rac to total Rac) through a mechanism that involved cAMP but was independent of PKA. Further pharmacologic analysis, combined with expression of various mutants of Rac, the Ras GTPase Rap1, and Epac1 (cAMP-activated guanine nucleotide exchange factor for Rap1), indicated that cAMP stimulated Epac1, which activated Rap1, which led to activation of Rac and sAPPα secretion. These data thus define a novel cAMP-dependent pathway involved in the regulation of sAPPα secretion.

M. Maillet, S. J. Robert, M. Cacquevel, M. Gastineau, D. Vivien, J. Bertoglio, J. L. Zugaza, R. Fischmeister, F. Lezoualc'h, Crosstalk between Rap1 and Rac regulates secretion of sAPPα. Nat. Cell. Biol. 5 633-639 (2003). [Online Journal]