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Vol. 14, Issue 12, 4846-4856, December 2003

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The GTP/GDP Cycling of Rho GTPase TCL Is an Essential Regulator of the Early Endocytic Pathway

Marion de Toledo ^*, Francesca Senic-Matuglia , Jean Salamero , Gilles Uze , Franck Comunale , Philippe Fort , and Anne Blangy  

^* Centre de Recherches en Biochimie Macromoléculaire, Centre National de la Recherche Scientifique Unité Propre de Recherche 1086, 34293 Montpellier, France; Institut de Génétique Moléculaire, Centre National de la Recherche Scientifique Unité Mixte Recherche 5124, 34293 Montpellier, France; and Institut Curie, Centre National de la Recherche Scientifique Unité Mixte Recherche 144, 75248 Paris, France

Submitted April 24, 2003; Revised August 1, 2003; Accepted August 20, 2003
Monitoring Editor: Anne Ridley

Rho GTPases are key regulators of actin dynamics. We report that the Rho GTPase TCL, which is closely related to Cdc42 and TC10, localizes to the plasma membrane and the early/sorting endosomes in HeLa cells, suggesting a role in the early endocytic pathway. Receptor-dependent internalization of transferrin (Tf) is unaffected by suppression of endogenous TCL by small interfering RNA treatment. However, Tf accumulates in Rab5-positive uncoated endocytic vesicles and fails to reach the early endosome antigen-1–positive early endosomal compartments and the pericentriolar recycling endosomes. Moreover, Tf release upon TCL knockdown is significantly slower. Conversely, in the presence of dominant active TCL, internalized Tf accumulates in early endosome antigen-1–positive early/sorting endosomes and not in perinuclear recycling endosomes. Tf recycles directly from the early/sorting endosomes and it is normally released by the cells. The same phenotype is generated by replacing the C terminus of dominant active Cdc42 and TC10 with that of TCL, indicating that all three proteins share downstream effector proteins. Thus, TCL is essential for clathrin-dependent endocytosed receptors to enter the early/sorting endosomes. Furthermore, the active GTPase favors direct recycling from early/sorting endosomes without accumulating in the perinuclear recycling endosomes.

Abbreviations used: CRIB, Cdc42/Rac interaction binding; da, dominant active; dn, dominant negative; EE/SE, early/sorting endosomes; EEA1, early endosome antigen-1; EGFR, epidermal growth factor receptor; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; GFP, green fluorescent protein; RE, recycling endosome; Tf, transferrin; TfR, transferrin receptor; wt, wild-type.

Corresponding author. E-mail address: blangy{at}crbm.cnrs-mop.fr.

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