PMID- 10022860
OWN - NLM
STAT- MEDLINE
DCOM- 19990325
LR  - 20190508
IS  - 0270-7306 (Print)
IS  - 0270-7306 (Linking)
VI  - 19
IP  - 3
DP  - 1999 Mar
TI  - Ral-specific guanine nucleotide exchange factor activity opposes other Ras
      effectors in PC12 cells by inhibiting neurite outgrowth.
PG  - 1731-41
AB  - 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 effectors. 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 approximately 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 effectors. 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 effectors and their temporal regulation may be important determinants
      for cell fate decisions between proliferation and differentiation.
FAU - Goi, T
AU  - Goi T
AD  - Department of Biochemistry, Tufts University School of Medicine, Boston,
      Massachusetts 02111, USA.
FAU - Rusanescu, G
AU  - Rusanescu G
FAU - Urano, T
AU  - Urano T
FAU - Feig, L A
AU  - Feig LA
LA  - eng
GR  - GM47707/GM/NIGMS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - Mol Cell Biol
JT  - Molecular and cellular biology
JID - 8109087
RN  - 0 (Guanine Nucleotide Exchange Factors)
RN  - 0 (Nerve Growth Factors)
RN  - 0 (Proteins)
RN  - 0 (Ralb protein, rat)
RN  - 0 (ras Guanine Nucleotide Exchange Factors)
RN  - 86-01-1 (Guanosine Triphosphate)
RN  - EC 3.6.1.- (GTP Phosphohydrolases)
RN  - EC 3.6.1.- (GTP-Binding Proteins)
RN  - EC 3.6.5.2 (ral GTP-Binding Proteins)
RN  - EC 3.6.5.2 (ras Proteins)
RN  - EC 3.6.5.2 (rho GTP-Binding Proteins)
SB  - IM
MH  - Animals
MH  - Cell Cycle
MH  - GTP Phosphohydrolases/metabolism
MH  - GTP-Binding Proteins/*metabolism
MH  - Gene Expression Regulation
MH  - Genes, fos
MH  - Guanine Nucleotide Exchange Factors
MH  - Guanosine Triphosphate/*metabolism
MH  - Mice
MH  - Nerve Growth Factors/pharmacology
MH  - Neurites/*physiology
MH  - PC12 Cells
MH  - Promoter Regions, Genetic
MH  - Proteins/*metabolism
MH  - Rabbits
MH  - Rats
MH  - ral GTP-Binding Proteins
MH  - ras Guanine Nucleotide Exchange Factors
MH  - ras Proteins/genetics/metabolism
MH  - rho GTP-Binding Proteins
PMC - PMC83966
EDAT- 1999/02/18 00:00
MHDA- 1999/02/18 00:01
CRDT- 1999/02/18 00:00
PHST- 1999/02/18 00:00 [pubmed]
PHST- 1999/02/18 00:01 [medline]
PHST- 1999/02/18 00:00 [entrez]
AID - 10.1128/mcb.19.3.1731 [doi]
PST - ppublish
SO  - Mol Cell Biol. 1999 Mar;19(3):1731-41. doi: 10.1128/mcb.19.3.1731.