title: A Gα-Stimulated RapGEF Is a Receptor-Proximal Regulator of Dictyostelium Chemotaxis.
abstract: Chemotaxis, or directional movement toward extracellular chemical gradients, is an important property of cells that is mediated through G-protein-coupled receptors (GPCRs). Although many chemotaxis pathways downstream of Gβγ have been identified, few Gα effectors are known. Gα effectors are of particular importance because they allow the cell to distinguish signals downstream of distinct chemoattractant GPCRs. Here we identify GflB, a Gα2 binding partner that directly couples the Dictyostelium cyclic AMP GPCR to Rap1. GflB localizes to the leading edge and functions as a Gα-stimulated, Rap1-specific guanine nucleotide exchange factor required to balance Ras and Rap signaling. The kinetics of GflB translocation are fine-tuned by GSK-3 phosphorylation. Cells lacking GflB display impaired Rap1/Ras signaling and actin and myosin dynamics, resulting in defective chemotaxis. Our observations demonstrate that GflB is an essential upstream regulator of chemoattractant-mediated cell polarity and cytoskeletal reorganization functioning to directly link Gα activation to monomeric G-protein signaling.
authors.affiliation: Department of Cell Biochemistry, University of Groningen, Nijenborgh 7, 9747 AG Groningen, the Netherlands.
authors.forename: Youtao
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Section of Cell and Developmental Biology, Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Jesus
authors.initials: J
authors.lastname: Lacal
authors.affiliation: MRC Laboratory of Molecular Biology, Cambridge CB2 0QH, UK.
authors.forename: Douwe M
authors.initials: DM
authors.lastname: Veltman
authors.affiliation: Department of Biochemistry, Netherlands Proteomics Centre, Groningen Biological Sciences and Biotechnology Institute, University of Groningen, 9747 AG Groningen, the Netherlands.
authors.forename: Fabrizia
authors.initials: F
authors.lastname: Fusetti
authors.affiliation: Department of Cell Biochemistry, University of Groningen, Nijenborgh 7, 9747 AG Groningen, the Netherlands.
authors.forename: Peter J M
authors.initials: PJ
authors.lastname: van Haastert
authors.affiliation: Section of Cell and Developmental Biology, Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Firtel
authors.affiliation: Department of Cell Biochemistry, University of Groningen, Nijenborgh 7, 9747 AG Groningen, the Netherlands. Electronic address: a.kortholt@rug.nl.
authors.forename: Arjan
authors.initials: A
authors.lastname: Kortholt
mesh_terms: D000199:Actins / Q000378:metabolism; D002633:Chemotaxis / Q000187:drug effects; D000242:Cyclic AMP / Q000494:pharmacology; D004023:Dictyostelium / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D044385:GTP-Binding Protein alpha Subunits / Q000378:metabolism*; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism*; D008954:Models, Biological; D024462:Myosin Type II / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D058105:Polymerization / Q000187:drug effects; D015800:Protozoan Proteins / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D018631:ras Proteins / Q000378:metabolism
chemical_list: D000199:Actins; D044385:GTP-Binding Protein alpha Subunits; D020662:Guanine Nucleotide Exchange Factors; D015800:Protozoan Proteins; D043562:Receptors, G-Protein-Coupled; D000242:Cyclic AMP; D038362:Glycogen Synthase Kinase 3; D024462:Myosin Type II; D018631:ras Proteins