title: The small GTP-binding proteins, Rac and Rho, regulate cytoskeletal organization and exocytosis in mast cells by parallel pathways.
abstract: In mast cells, activation of GTP-binding proteins induces centripetal reorganization of actin filaments. This effect is due to disassembly, relocalization, and polymerization of F-actin and is dependent on two small GTPases, Rac and Rho. Activities of Rac and Rho are also essential for the secretory function of mast cells. In response to GTP-gamma-S and/or calcium, only a proportion of permeabilized mast cells is capable of secretory response. Here, we have compared actin organization of secreting and nonsecreting cell populations. We show that the cytoskeletal and secretory responses are strongly correlated, indicating a common upstream regulator of the two functions. The secreting cell population preferentially displays both relocalization and polymerization of actin. However, when actin relocalization or polymerization is inhibited by phalloidin or cytochalasin, respectively, secretion is unaffected. Moreover, the ability of the constitutively active mutants of Rac and Rho to enhance secretion is also unaffected in the presence of cytochalasin. Therefore, Rac and Rho control these two functions by divergent, parallel signaling pathways. Cortical actin disassembly occurs in both secreting and nonsecreting populations and does not, by itself, induce exocytosis. A model for the control of exocytosis is proposed that includes at least four GTP-binding proteins and suggests the presence of both shared and divergent signaling pathways from Rac and Rho.
authors.affiliation: Physiology Department, University College London, United Kingdom.
authors.forename: J C
authors.initials: JC
authors.lastname: Norman
authors.forename: L S
authors.initials: LS
authors.lastname: Price
authors.forename: A J
authors.initials: AJ
authors.lastname: Ridley
authors.forename: A
authors.initials: A
authors.lastname: Koffer
mesh_terms: D000199:Actins / Q000502:physiology; D000818:Animals; D001896:Boron Compounds; D002463:Cell Membrane Permeability; D002478:Cells, Cultured; D003208:Concanavalin A / Q000378:metabolism; D003572:Cytochalasins / Q000494:pharmacology; D003599:Cytoskeleton / Q000378:metabolism / Q000648:ultrastructure*; D005089:Exocytosis / Q000187:drug effects / Q000502:physiology*; D005434:Flow Cytometry / Q000379:methods; D016650:Fluorescein-5-isothiocyanate / Q000031:analogs & derivatives; D019204:GTP-Binding Proteins / Q000187:drug effects / Q000378:metabolism*; D020690:GTPase-Activating Proteins; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000494:pharmacology; D006153:Guanosine Diphosphate / Q000031:analogs & derivatives / Q000494:pharmacology; D008407:Mast Cells / Q000378:metabolism / Q000502:physiology* / Q000648:ultrastructure; D018613:Microscopy, Confocal / Q000379:methods; D011506:Proteins / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D013194:Staining and Labeling / Q000379:methods; D013873:Thionucleotides / Q000494:pharmacology; D001619:beta-N-Acetylhexosaminidases / Q000378:metabolism; D020744:rac GTP-Binding Proteins; D020741:rho GTP-Binding Proteins; D020742:rhoA GTP-Binding Protein
chemical_list: C095489:4,4-difluoro-4-bora-3a,4a-diaza-s-indacene; D000199:Actins; D001896:Boron Compounds; D003572:Cytochalasins; D020690:GTPase-Activating Proteins; D011506:Proteins; D013873:Thionucleotides; C042784:fluorescein isothiocyanate-concanavalin A; D003208:Concanavalin A; D006153:Guanosine Diphosphate; D016244:Guanosine 5'-O-(3-Thiotriphosphate); C023427:guanosine 5'-O-(2-thiodiphosphate); D001619:beta-N-Acetylhexosaminidases; D019204:GTP-Binding Proteins; D020744:rac GTP-Binding Proteins; D020741:rho GTP-Binding Proteins; D020742:rhoA GTP-Binding Protein; D016650:Fluorescein-5-isothiocyanate