Modulation of Rac localization and function by dynamin
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 complexe...
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| Veröffentlicht in: | Molecular biology of the cell 2004-01, Vol.15 (1), p.256-267 |
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| container_title | Molecular biology of the cell |
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| creator | Schlunck, Günther Damke, Hanna Kiosses, William B Rusk, Nicole Symons, Marc H Waterman-Storer, Clare M Schmid, Sandra L Schwartz, Martin Alexander |
| description | 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 small interfering RNA 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. Fluorescence resonance energy transfer 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 wild-type GFP-Rac was found on macropinosomes and Rac-dependent, platelet-derived growth factor-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. |
| doi_str_mv | 10.1091/mbc.E03-01-0019 |
| format | Article |
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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 small interfering RNA 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. Fluorescence resonance energy transfer 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 wild-type GFP-Rac was found on macropinosomes and Rac-dependent, platelet-derived growth factor-induced macropinocytosis was abolished by Dyn2(K44A) expression. 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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 small interfering RNA 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. Fluorescence resonance energy transfer 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 wild-type GFP-Rac was found on macropinosomes and Rac-dependent, platelet-derived growth factor-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.</description><subject>Animals</subject><subject>Cell Adhesion - physiology</subject><subject>Cell Movement - physiology</subject><subject>Cells, Cultured</subject><subject>Dynamin II - drug effects</subject><subject>Dynamin II - metabolism</subject><subject>Dynamin II - physiology</subject><subject>Fibronectins - metabolism</subject><subject>Fluorescence Resonance Energy Transfer</subject><subject>Mice</subject><subject>Mutation</subject><subject>NIH 3T3 Cells</subject><subject>Protein-Serine-Threonine Kinases - metabolism</subject><subject>Protein-Serine-Threonine Kinases - physiology</subject><subject>Proto-Oncogene Proteins c-akt</subject><subject>Pseudopodia - metabolism</subject><subject>Rats</subject><subject>Recombinant Fusion Proteins - drug effects</subject><subject>Recombinant Fusion Proteins - metabolism</subject><subject>Recombinant Fusion Proteins - physiology</subject><subject>RNA, Small Interfering - pharmacology</subject><issn>1059-1524</issn><issn>1939-4586</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2004</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpFkEtLw0AURgdRbK2u3UlW7qadO69kllLqAyqC6HqYJ0SSTM00i_rrTU3B1b3349xvcRC6BbIEomDVWrfcEIYJYEJAnaE5KKYwF5U8H3ciFAZB-Qxd5fw1EpzL8hLNgEsoKwpzJF-THxqzr1NXpFi8G1c0yZmm_pky0_kiDp37O-yh8IfOtHV3jS6iaXK4Oc0F-nzcfKyf8fbt6WX9sMWOl3KPI3WGeqcClVEQrkBR6RmzhoQSrGUli54z50BYG4F77wPj1FTCOiMCcLZA91Pvrk_fQ8h73dbZhaYxXUhD1hUhpVKCjuBqAl2fcu5D1Lu-bk1_0ED0UZUeVelAmCagj6rGj7tT9WDb4P_5kxv2C3xQZPo</recordid><startdate>200401</startdate><enddate>200401</enddate><creator>Schlunck, Günther</creator><creator>Damke, Hanna</creator><creator>Kiosses, William B</creator><creator>Rusk, Nicole</creator><creator>Symons, Marc H</creator><creator>Waterman-Storer, Clare M</creator><creator>Schmid, Sandra L</creator><creator>Schwartz, Martin Alexander</creator><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope></search><sort><creationdate>200401</creationdate><title>Modulation of Rac localization and function by dynamin</title><author>Schlunck, Günther ; 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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 small interfering RNA 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. Fluorescence resonance energy transfer 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. 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| subjects | Animals Cell Adhesion - physiology Cell Movement - physiology Cells, Cultured Dynamin II - drug effects Dynamin II - metabolism Dynamin II - physiology Fibronectins - metabolism Fluorescence Resonance Energy Transfer Mice Mutation NIH 3T3 Cells Protein-Serine-Threonine Kinases - metabolism Protein-Serine-Threonine Kinases - physiology Proto-Oncogene Proteins c-akt Pseudopodia - metabolism Rats Recombinant Fusion Proteins - drug effects Recombinant Fusion Proteins - metabolism Recombinant Fusion Proteins - physiology RNA, Small Interfering - pharmacology |
| title | Modulation of Rac localization and function by dynamin |
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