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© The Rockefeller University Press, 0021-9525/1997//797 $5.00
The Journal of Cell Biology, Volume 139, Number 3, , 1997 797-807

Article

The Guanine Nucleotide Exchange Factor Tiam1 Affects Neuronal Morphology; Opposing Roles for the Small GTPases Rac and Rho



Frank N. van Leeuwen*, Hendrie E.T. Kain*, Rob A. van der Kammen*, Frits Michiels*, Onno W. Kranenburg{ddagger}, and John G. Collard*

The Netherlands Cancer Institute, Antoni van Leeuwenhoekhuis, * Division of Cell Biology, {ddagger} Division of Cellular Biochemistry, 1066 CX Amsterdam, The Netherlands

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 {alpha}6β1 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.

Abbreviations used in this paper: GAP, GTPase activating protein; GEF, guanine nucleotide exchange factor; LPA, lysophosphatidic acid; NGF, nerve growth factor; Tiam1, T-lymphoma invasion and metastasis 1.

Address all correspondence to Dr. J.G. Collard, The Netherlands Cancer Institute, Division of Cell Biology (H1), Plesmanlaan 121, 1066 XC Amsterdam, The Netherlands. Fax: (+31) 20 512 1944. E-mail: JCOLL@ NKI.NL


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