title: Role of phosphatidylinositol 3' kinase and a downstream pleckstrin homology domain-containing protein in controlling chemotaxis in dictyostelium.
abstract: We show that cells lacking two Dictyostelium class I phosphatidylinositol (PI) 3' kinases (PI3K and pi3k1/2-null cells) or wild-type cells treated with the PI3K inhibitor LY294002 are unable to properly polarize, are very defective in the temporal, spatial, and quantitative regulation of chemoattractant-mediated filamentous (F)-actin polymerization, and chemotax very slowly. PI3K is thought to produce membrane lipid-binding sites for localization of PH domain-containing proteins. We demonstrate that in response to chemoattractants three PH domain-containing proteins do not localize to the leading edge in pi3k1/2-null cells, and the translocation is blocked in wild-type cells by LY294002. Cells lacking one of these proteins, phdA-null cells, exhibit defects in the level and kinetics of actin polymerization at the leading edge and have chemotaxis phenotypes that are distinct from those described previously for protein kinase B (PKB) (pkbA)-null cells. Phenotypes of PhdA-dominant interfering mutations suggest that PhdA is an adaptor protein that regulates F-actin localization in response to chemoattractants and links PI3K to the control of F-actin polymerization at the leading edge during pseudopod formation. We suggest that PKB and PhdA lie downstream from PI3K and control different downstream effector pathways that are essential for proper chemotaxis.
authors.affiliation: Section of Cell and Developmental Biology and Center for Molecular Genetics, University of California at San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.
authors.forename: S
authors.initials: S
authors.lastname: Funamoto
authors.forename: K
authors.initials: K
authors.lastname: Milan
authors.forename: R
authors.initials: R
authors.lastname: Meili
authors.forename: R A
authors.initials: RA
authors.lastname: Firtel
mesh_terms: D000199:Actins / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D001798:Blood Proteins / Q000737:chemistry* / Q000235:genetics; D002633:Chemotaxis / Q000187:drug effects / Q000502:physiology*; D002867:Chromones / Q000494:pharmacology; D004023:Dictyostelium / Q000166:cytology* / Q000201:enzymology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005492:Folic Acid; D007700:Kinetics; D018715:Microscopy, Video; D008969:Molecular Sequence Data; D009025:Morpholines / Q000494:pharmacology; D016254:Mutagenesis, Insertional / Q000502:physiology; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010750:Phosphoproteins / Q000737:chemistry* / Q000235:genetics; D011108:Polymers / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases; D017434:Protein Structure, Tertiary; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D015800:Protozoan Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism
chemical_list: D000199:Actins; D001798:Blood Proteins; D002867:Chromones; D004791:Enzyme Inhibitors; D005492:Folic Acid; D009025:Morpholines; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010750:Phosphoproteins; D011108:Polymers; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D015800:Protozoan Proteins; C428644:PhdA protein, Dictyostelium; C039077:platelet protein P47; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one