Nucleotide exchange factor GEF-H1 mediates cross-talk between microtubules and the actin cytoskeleton.
Regulation of the actin cytoskeleton by microtubules is mediated by the Rho family GTPases. However, the molecular mechanisms that link microtubule dynamics to Rho GTPases have not, as yet, been identified. Here we show that the Rho guanine nucleotide exchange factor (GEF)-H1 is regulated by an interaction with microtubules. GEF-H1 mutants that are deficient in microtubule binding have higher activity levels than microtubule-bound forms. These mutants also induce Rho-dependent changes in cell morphology and actin organization. Furthermore, drug-induced microtubule depolymerization induces changes in cell morphology and gene expression that are similar to the changes induced by the expression of active forms of GEF-H1. Furthermore, these effects are inhibited by dominant-negative versions of GEF-H1. Thus, GEF-H1 links changes in microtubule integrity to Rho-dependent regulation of the actin cytoskeleton.
Krendel
Mira
M
Department of Immunology, The Scripps Research Institute, 10550 N. Torrey Pines Road, La Jolla, CA 92037, USA.
Zenke
Frank T
FT
Bokoch
Gary M
GM
D000199:Actins / Q000378:metabolism*; D000818:Animals; D019556:COS Cells; D018076:DNA, Complementary / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D020662:Guanine Nucleotide Exchange Factors / Q000737:chemistry* / Q000378:metabolism*; D006150:Guanine Nucleotides; D006367:HeLa Cells; D006801:Humans; D008856:Microscopy, Fluorescence; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D008870:Microtubules / Q000378:metabolism*; D008957:Models, Genetic; D010957:Plasmids / Q000378:metabolism; D011233:Precipitin Tests; D017434:Protein Structure, Tertiary; D064067:Rho Guanine Nucleotide Exchange Factors; D013997:Time Factors; D014162:Transfection; D020764:cdc42 GTP-Binding Protein / Q000378:metabolism; D020830:rac1 GTP-Binding Protein / Q000378:metabolism; D020703:ras GTPase-Activating Proteins / Q000378:metabolism; D020663:ras Guanine Nucleotide Exchange Factors / Q000737:chemistry* / Q000378:metabolism*; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
C577356:ARHGEF2 protein, human; D000199:Actins; D018076:DNA, Complementary; D020662:Guanine Nucleotide Exchange Factors; D006150:Guanine Nucleotides; D008869:Microtubule-Associated Proteins; D064067:Rho Guanine Nucleotide Exchange Factors; D020703:ras GTPase-Activating Proteins; D020663:ras Guanine Nucleotide Exchange Factors; D020764:cdc42 GTP-Binding Protein; D020830:rac1 GTP-Binding Protein; D020742:rhoA GTP-Binding Protein