Abstract
Cell polarity is essential for cell division, cell differentiation, and most differentiated cell functions including cell migration. The small G protein Cdc42 controls cell polarity in a wide variety of cellular contexts. Although restricted localization of active Cdc42 seems to be important for its distinct functions, mechanisms responsible for the concentration of active Cdc42 at precise cortical sites are not fully understood. In this study, we show that during directed cell migration, Cdc42 accumulation at the cell leading edge relies on membrane traffic. Cdc42 and its exchange factor βPIX localize to intracytosplasmic vesicles. Inhibition of Arf6-dependent membrane trafficking alters the dynamics of Cdc42-positive vesicles and abolishes the polarized recruitment of Cdc42 and βPIX to the leading edge. Furthermore, we show that Arf6-dependent membrane dynamics is also required for polarized recruitment of Rac and the Par6-aPKC polarity complex and for cell polarization. Our results demonstrate influence of membrane dynamics on the localization and activation of Cdc42 and consequently on directed cell migration.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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ADP-Ribosylation Factor 6
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ADP-Ribosylation Factors / genetics
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ADP-Ribosylation Factors / metabolism
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Adaptor Proteins, Signal Transducing
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Adenomatous Polyposis Coli Protein / metabolism
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Animals
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Astrocytes / cytology
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Astrocytes / metabolism
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Carrier Proteins / metabolism
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Cell Membrane / metabolism*
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Cell Movement / physiology*
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Cell Polarity / physiology*
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Cell Surface Extensions / metabolism
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Cells, Cultured
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Centrosome / metabolism
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Endosomes / metabolism
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Golgi Apparatus / metabolism
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Guanine Nucleotide Exchange Factors / metabolism
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Microtubules / metabolism
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Models, Biological
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Protein Kinase C / metabolism
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Protein Transport / physiology*
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RNA, Small Interfering / genetics
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Rats
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Rats, Inbred Strains
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Rho Guanine Nucleotide Exchange Factors
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Transport Vesicles / metabolism*
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Wound Healing / physiology
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cdc42 GTP-Binding Protein / metabolism*
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rab5 GTP-Binding Proteins / genetics
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rac1 GTP-Binding Protein / genetics
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rac1 GTP-Binding Protein / metabolism
Substances
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ADP-Ribosylation Factor 6
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Adaptor Proteins, Signal Transducing
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Adenomatous Polyposis Coli Protein
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Carrier Proteins
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Guanine Nucleotide Exchange Factors
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Pard6a protein, rat
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RNA, Small Interfering
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Rho Guanine Nucleotide Exchange Factors
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PKC-3 protein
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Protein Kinase C
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Rac1 protein, rat
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ADP-Ribosylation Factors
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Arf6 protein, rat
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cdc42 GTP-Binding Protein
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rab5 GTP-Binding Proteins
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rac1 GTP-Binding Protein