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A more recent version of this article appeared on January 1, 2004
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Submitted on January 17, 2003
Revised on September 3, 2003
Accepted on September 8, 2003
1 Div. of Vascular Biology, The Scripps Research Institute, La Jolla, California 92037; Present Address: University Eye Hospital, Div.
Experimental Ophthalmology, Josef-Schneider Str. 11, D 97080
Würzburg, Germany
2 Dept. of Cell Biology, The Scripps Research Institute, La Jolla, California 92037
3 Div. of Vascular Biology, The Scripps Research Institute, La Jolla, California 92037
4 Center for Oncology and Cell Biology, North Shore-Long Island Jewish Research Institute, Manhasset, New York 11030
5 Div. of Vascular Biology, The Scripps Research Institute, La Jolla, California 92037; Present Address: Dept. of Microbiology and Cardiovascular
Research Center, University of Virginia, Charlottesville, VA 22908, M.A. Schwartz, Cardiovascular Research Center,
University of Virginia, MR5, 415 Lane Road, Charlottesville, VA 22908
* Corresponding author. E-mail address: maschwartz{at}virginia.edu.
The GTPase dynamin controls a variety of endocytic pathways, participates in the formation of phagosomes, podosomal adhesions and invadopodia and in regulation of the cytoskeleton and apoptosis. Rac, a member of the Rho family of small GTPases, controls formation of lamellipodia and focal complexes, which are critical in cell migration and phagocytosis. We now show that disruption of dynamin-2 function alters Rac localization and inhibits cell spreading and lamellipodia formation even though Rac is activated. Dominant-negative K44A dynamin-2 inhibited cell spreading and lamellipodia formation on fibronectin without blocking cell adhesion; dynamin-2 depletion by specific siRNA inhibited lamellipodia in a similar manner. Dyn2(K44A) induced Rac mislocalization away from cell edges, into abnormal dorsal ruffles and led to increased total Rac activity. FRET-imaging of Rac activity confirmed its predominant localization to aberrant dorsal ruffles in the presence of dominant negative dyn2(K44A). Dyn2(K44A) induced the accumulation of tubulated structures bearing membrane-bound Rac-GFP. Constitutively active but not WT GFP-Rac was found on macropinosomes and Rac-dependent, platelet-derived growth factor (PDGF)-induced macropinocytosis was abolished by Dyn2(K44A) expression. These data suggest an indispensable role of dynamin in Rac trafficking to allow for lamellipodia formation and cell spreading.
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