scholarly journals Phosphorylation of p85 βPIX, a Rac/Cdc42-specific Guanine Nucleotide Exchange Factor, via the Ras/ERK/PAK2 Pathway Is Required for Basic Fibroblast Growth Factor-induced Neurite Outgrowth

2002 ◽  
Vol 277 (46) ◽  
pp. 44417-44430 ◽  
Author(s):  
Eun-Young Shin ◽  
Kyung-Sun Shin ◽  
Chan-Soo Lee ◽  
Kyung-Nam Woo ◽  
Song-Hua Quan ◽  
...  
Keyword(s):  
Growth Factor ◽  
Neurite Outgrowth ◽  
Fibroblast Growth Factor ◽  
Basic Fibroblast Growth Factor ◽  
Guanine Nucleotide Exchange Factor ◽  
Guanine Nucleotide ◽  
Fibroblast Growth ◽  
Nucleotide Exchange ◽  
Guanine Nucleotide Exchange ◽  
Nucleotide Exchange Factor

scholarly journals Ras activation by insulin and epidermal growth factor through enhanced exchange of guanine nucleotides on p21ras

1993 ◽  
Vol 13 (1) ◽  
pp. 155-162
Author(s):  
R H Medema ◽  
A M de Vries-Smits ◽  
G C van der Zon ◽  
J A Maassen ◽  
J L Bos
Keyword(s):  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Guanine Nucleotide Exchange Factor ◽  
Nucleotide Binding ◽  
Guanine Nucleotide ◽  
Nucleotide Exchange ◽  
Exchange Factor ◽  
Guanine Nucleotide Exchange ◽  
Nucleotide Exchange Factor ◽  
Epidermal Growth

A number of growth factors, including insulin and epidermal growth factor (EGF), induce accumulation of the GTP-bound form of p21ras. This accumulation could be caused either by an increase in guanine nucleotide exchange on p21ras or by a decrease in the GTPase activity of p21ras. To investigate whether insulin and EGF affect nucleotide exchange on p21ras, we measured binding of [alpha-32P]GTP to p21ras in cells permeabilized with streptolysin O. For this purpose, we used a cell line which expressed elevated levels of p21 H-ras and which was highly responsive to insulin and EGF. Stimulation with insulin or EGF resulted in an increase in the rate of nucleotide binding to p21ras. To determine whether this increased binding rate is due to the activation of a guanine nucleotide exchange factor, we made use of the inhibitory properties of a dominant negative mutant of p21ras, p21ras (Asn-17). Activation of p21ras by insulin and EGF in intact cells was abolished in cells infected with a recombinant vaccinia virus expressing p21ras (Asn-17). In addition, the enhanced nucleotide binding to p21ras in response to insulin and EGF in permeabilized cells was blocked upon expression of p21ras (Asn-17). From these data, we conclude that the activation of a guanine nucleotide exchange factor is involved in insulin- and EGF-induced activation of p21ras.

scholarly journals GEFT, A Rho Family Guanine Nucleotide Exchange Factor, Regulates Neurite Outgrowth and Dendritic Spine Formation

2004 ◽  
Vol 279 (44) ◽  
pp. 45824-45832 ◽  
Author(s):  
Brad Bryan ◽  
Vikas Kumar ◽  
Lewis Joe Stafford ◽  
Yi Cai ◽  
Gangyi Wu ◽  
...  
Keyword(s):  
Neurite Outgrowth ◽  
Dendritic Spine ◽  
Neuroblastoma Cells ◽  
Guanine Nucleotide Exchange Factor ◽  
Guanine Nucleotide ◽  
Nucleotide Exchange ◽  
Spine Formation ◽  
Guanine Nucleotide Exchange ◽  
Nucleotide Exchange Factor ◽  
Rho Family

The Rho family of small GTPases controls a wide range of cellular processes in eukaryotic cells, such as normal cell growth, proliferation, differentiation, gene regulation, actin cytoskeletal organization, cell fate determination, and neurite outgrowth. The activation of Rho-GTPases requires the exchange of GDP for GTP, a process catalyzed by the Dbl family of guanine nucleotide exchange factors. We demonstrate that a newly identified guanine nucleotide exchange factor, GEFT, is widely expressed in the brain and highly concentrated in the hippocampus, and the Purkinje and granular cells of the cerebellum. Exogenous expression of GEFT promotes dendrite outgrowth in hippocampal neurons, resulting in spines with larger size as compared with control spines. In neuroblastoma cells, GEFT promotes the active GTP-bound state of Rac1, Cdc42, and RhoA and increases neurite outgrowth primarily via Rac1. Furthermore, we demonstrated that PAK1 and PAK5, both downstream effectors of Rac1/Cdc42, are necessary for GEFT-induced neurite outgrowth. AP-1 and NF-κB, two transcriptional factors involved in neurite outgrowth and survival, were up-regulated in GEFT-expressing cells. Together, our data suggest that GEFT enhances dendritic spine formation and neurite outgrowth in primary neurons and neuroblastoma cells, respectively, through the activation of Rac/Cdc42-PAK signaling pathways.

scholarly journals Integration of Transforming Growth Factor β and RAS Signaling Silences a RAB5 Guanine Nucleotide Exchange Factor and Enhances Growth Factor-Directed Cell Migration

2007 ◽  
Vol 28 (5) ◽  
pp. 1573-1583 ◽  
Author(s):  
Hailiang Hu ◽  
Marc Milstein ◽  
Joanne M. Bliss ◽  
Minh Thai ◽  
Gautam Malhotra ◽  
...  
Keyword(s):  
Growth Factor ◽  
Transforming Growth Factor ◽  
Guanine Nucleotide Exchange Factor ◽  
Transforming Growth Factor Β ◽  
Ras Signaling ◽  
Guanine Nucleotide ◽  
Nucleotide Exchange ◽  
Exchange Factor ◽  
Guanine Nucleotide Exchange ◽  
Nucleotide Exchange Factor

ABSTRACT Transforming growth factor β (TGF-β) receptor (TβR) signaling contributes to normal development as well as tumorigenesis. Here we report that RIN1, a RAB5 guanine nucleotide exchange factor (GEF) and down regulator of receptor tyrosine kinases (RTKs), promotes TβR signaling through enhanced endocytosis. TβR activation induces SNAI1 (Snail), a transcription repressor that reduces RIN1 expression, providing a negative feedback mechanism to control TβR trafficking and downstream signaling. Persistent RAS signaling disrupts this equilibrium by stabilizing SNAI1 protein, resulting in strong silencing of RIN1 and stabilization of RTKs. TGF-β-induced RIN1 silencing in breast cancer cells prolonged sensitivity to hepatocyte growth factor, a ligand for the MET-type RTK, and enhanced growth factor-directed cell motility. We conclude that in some tumor cells TβR and RAS signals are integrated through the silencing of RIN1, leading to a reduction in RAB5-mediated endocytosis. These findings shed new light on the basis for distinct interpretations of TGF-β signaling by normal versus transformed cells.

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