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J. Cell Biol.,
Volume 139, Number 3, November 3, 1997 797-807
The Netherlands Cancer Institute, Antoni van Leeuwenhoekhuis, * Division of Cell Biology, The invasion-inducing T-lymphoma invasion
and metastasis 1 (Tiam1) protein functions as a guanine
nucleotide exchange factor (GEF) for the small GTPase
Rac1. Differentiation-dependent expression of Tiam1
in the developing brain suggests a role for this GEF and
its effector Rac1 in the control of neuronal morphology.
Here we show that overexpression of Tiam1 induces
cell spreading and affects neurite outgrowth in N1E-115
neuroblastoma cells. These effects are Rac-dependent
and strongly promoted by laminin. Overexpression of
Tiam1 recruits the Division of Cellular Biochemistry,
1066 CX Amsterdam, The Netherlands
6
1 integrin, a laminin receptor, to
specific adhesive contacts at the cell periphery, which
are different from focal contacts. Cells overexpressing
Tiam1 no longer respond to lysophosphatidic acid-
induced neurite retraction and cell rounding, processes
mediated by Rho, suggesting that Tiam1-induced activation of Rac antagonizes Rho signaling. This inhibition can be overcome by coexpression of constitutively
active RhoA, which may indicate that regulation occurs
at the level of Rho or upstream. Conversely, neurite
formation induced by Tiam1 or Rac1 is further promoted by inactivating Rho. These results demonstrate
that Rac- and Rho-mediated pathways oppose each
other during neurite formation and that a balance between these pathways determines neuronal morphology. Furthermore, our data underscore the potential
role of Tiam1 as a specific regulator of Rac during neurite formation and illustrate the importance of reciprocal interactions between the cytoskeleton and the extracellular matrix during this process.
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