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Ral-specific cuanine nucleotide exchange factor activity opposes other Ras effectors in PC12 cells by inhibiting neurite outgrowth

Domenii publicaţii > Biologie + Tipuri publicaţii > Articol în revistã ştiinţificã

Autori: Goi T, Rusanescu G, Urano T, Feig LA

Editorial: MOL CELL BIOL, 19 (3), p.1731-1741, 1999.

Rezumat:

Ras proteins can activate at least three classes of downstream target proteins: Raf kinases, phosphatidylinositol-3 phosphate (PI3) kinase, and Ral-specific guanine
nucleotide exchange factors (Ral-GEFs). In NIH 3T3 cells, activated Ral-GEFs contribute to Ras-induced cell proliferation and oncogenic transformation by
complementing the activities of Raf and PI3 kinases. In PC12 cells, activated Raf and PI3 kinases mediate Ras-induced cell cycle arrest and differentiation into a
neuronal phenotype. Here, we show that in PC12 cells, Ral-GEF activity acts opposite to other Ras effecters. Elevation of Ral-GEF activity induced by transfection of a
mutant Ras protein that preferentially activates Ral-GEFs, or by transfection of the catalytic domain of the Ral-GEF Rgr, suppressed cell cycle arrest and neurite
outgrowth induced by nerve growth factor (NGF) treatment. In addition, Rgr reduced neurite outgrowth induced by a mutant Ras protein that preferentially activates Raf
kinases. Furthermore, inhibition of Ral-GEF activity by expression of a dominant negative Ral mutant accelerated cell cycle arrest and enhanced neurite outgrowth in
response to NGF treatment. Ral-GEF activity may function, at least in part, through inhibition of the Rho family GTPases, CDC42 and Rac. In contrast to Ras, which
was activated for hours by NGF treatment, Ral was activated for only similar to 20 min. These findings suggest that one function of Ral-GEF signaling induced by NGF
is to delay the onset of cell cycle arrest and neurite outgrowth induced by other Ras effecters. They also demonstrate that Ras has the potential to promote both
antidifferentiation and prodifferentiation signaling pathways through activation of distinct effector proteins. Thus, in some cell types the ratio of activities among Ras
effecters and their temporal regulation may be important determinants for cell fate decisions between proliferation and differentiation.

Cuvinte cheie: GDP DISSOCIATION STIMULATOR, C-FOS PROMOTER, NEURONAL DIFFERENTIATION, PHOSPHOLIPASE-D, CYCLE ARREST, MAP KINASE,