Una nueva funcion para un GEF

DANIEL HOCHBAUM; TAMARA TANOS; DANIEL L. ALTSCHULER; OMAR A. COSO

Congreso; Sociedad Argentina de Investigación Bioquímica y Biología Molecular; 2001

Different cellular processes, such as growth, death or differentiation occur through cascades of proteins, which activates one to the other, and in general, alters the expression of target genes. One of the best characterized systems involve small G proteins, which oscillate between a GTP active state and a GDP inactive one. The removal of the GDP, and the subsequent binding of the GTP, is a process catalizated by guanosine nucleotide exchange factors (GEFs), that are activated in response to agonists, or by direct binding of diffusible molecules like cAMP, DAG or calcium. A weak GTPase activity of the small G protein can be increased by GAPs (GTPase activating proteins). In this study, we show that a GEF called EPAC (exchange protein direct activated by cAMP), specific for Rap proteins (a Ras-like family of small G proteins) can activate the c-Jun N-terminal kinase (JNK), independently of its exchange activity. This finding is supported by the followings results: 1) Overexpression of Rap1 G12V, a constitutive active Rap1, can?t activate JNK; 2) ΔEPAC, a constitutive active form of EPAC, which lacks the regulatory domain of cAMP binding, activates JNK to the same levels as EPAC WT; 3) RapGAP or Rap1N17 (a dominant negative form of Rap1) aren?t able to block EPAC-mediated activation of JNK; 4) N-EPAC, a mutant of EPAC lacking the GEF domain is able to activate JNK at even higher levels than full length EPAC.