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Division of Cellular Biochemistry, The Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands
The small GTP-binding protein Rho has
been implicated in the control of neuronal morphology.
In N1E-115 neuronal cells, the Rho-inactivating C3
toxin stimulates neurite outgrowth and prevents actomyosin-based neurite retraction and cell rounding
induced by lysophosphatidic acid (LPA), sphingosine1-phosphate, or thrombin acting on their cognate G
protein-coupled receptors. We have identified a novel
putative GDP/GTP exchange factor, RhoGEF (190 kD), that interacts with both wild-type and activated
RhoA, but not with Rac or Cdc42. RhoGEF, like activated RhoA, mimics receptor stimulation in inducing
cell rounding and in preventing neurite outgrowth. Furthermore, we have identified a 116-kD protein, p116Rip,
that interacts with both the GDP- and GTP-bound
forms of RhoA in N1E-115 cells. Overexpression of
p116Rip stimulates cell flattening and neurite outgrowth
in a similar way to dominant-negative RhoA and C3
toxin. Cells overexpressing p116Rip fail to change their
shape in response to LPA, as is observed after Rho inactivation. Our results indicate that (a) RhoGEF may link G protein-coupled receptors to RhoA activation
and ensuing neurite retraction and cell rounding; and
(b) p116Rip inhibits RhoA-stimulated contractility and
promotes neurite outgrowth.
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