Plexin-B1 directly interacts with PDZ-RhoGEF/LARG to regulate RhoA and growth cone morphology.
Plexins are widely expressed transmembrane proteins that, in the nervous system, mediate repulsive signals of semaphorins. However, the molecular nature of plexin-mediated signal transduction remains poorly understood. Here, we demonstrate that plexin-B family members associate through their C termini with the Rho guanine nucleotide exchange factors PDZ-RhoGEF and LARG. Activation of plexin-B1 by semaphorin 4D regulates PDZ-RhoGEF/LARG activity leading to RhoA activation. In addition, a dominant-negative form of PDZ-RhoGEF blocks semaphorin 4D-induced growth cone collapse in primary hippocampal neurons. Our study indicates that the interaction of mammalian plexin-B family members with the multidomain proteins PDZ-RhoGEF and LARG represents an essential molecular link between plexin-B and localized, Rho-mediated downstream signaling events which underly various plexin-mediated cellular phenomena including axonal growth cone collapse.
Institute of Pharmacology, University of Heidelberg, Im Neuenheimer Feld 366, Germany.
Jakub M
JM
Swiercz
Rohini
R
Kuner
Jürgen
J
Behrens
Stefan
S
Offermanns
D000818:Animals; D015703:Antigens, CD; D002450:Cell Communication / Q000235:genetics*; D002454:Cell Differentiation / Q000235:genetics*; D002462:Cell Membrane / Q000378:metabolism; D002478:Cells, Cultured; D002642:Chick Embryo; D005333:Fetus; D020439:Growth Cones / Q000378:metabolism* / Q000648:ultrastructure; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000378:metabolism*; D006624:Hippocampus / Q000196:embryology* / Q000254:growth & development / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding / Q000235:genetics; D017434:Protein Structure, Tertiary / Q000235:genetics; D051381:Rats; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism*; D012165:Retinal Ganglion Cells / Q000166:cytology / Q000378:metabolism; D064067:Rho Guanine Nucleotide Exchange Factors; D039961:Semaphorins; D015398:Signal Transduction / Q000235:genetics*; D020742:rhoA GTP-Binding Protein / Q000235:genetics / Q000378:metabolism*
C577222:ARHGEF12 protein, human; D015703:Antigens, CD; C093224:CD100 antigen; D020662:Guanine Nucleotide Exchange Factors; D008562:Membrane Glycoproteins; D009419:Nerve Tissue Proteins; C492119:PLXNB1 protein, human; C403525:RAPGEF2 protein, human; D011956:Receptors, Cell Surface; D064067:Rho Guanine Nucleotide Exchange Factors; D039961:Semaphorins; D020742:rhoA GTP-Binding Protein