title: Protein kinase A regulates the Ras, Rap1 and TORC2 pathways in response to the chemoattractant cAMP inDictyostelium.
abstract: Efficient directed migration requires tight regulation of chemoattractant signal transduction pathways in both space and time, but the mechanisms involved in such regulation are not well understood. Here, we investigated the role of protein kinase A (PKA) in controlling signaling of the chemoattractant cAMP inDictyostelium discoideumWe found that cells lacking PKA display severe chemotaxis defects, including impaired directional sensing. Although PKA is an important regulator of developmental gene expression, including the cAMP receptor cAR1, our studies using exogenously expressed cAR1 in cells lacking PKA, cells lacking adenylyl cyclase A (ACA) and cells treated with the PKA-selective pharmacological inhibitor H89, suggest that PKA controls chemoattractant signal transduction, in part, through the regulation of RasG, Rap1 and TORC2. As these pathways control the ACA-mediated production of intracellular cAMP, they lie upstream of PKA in this chemoattractant signaling network. Consequently, we propose that the PKA-mediated regulation of the upstream RasG, Rap1 and TORC2 signaling pathways is part of a negative feedback mechanism controlling chemoattractant signal transduction duringDictyosteliumchemotaxis.
authors.affiliation: Department of Chemistry and Biochemistry, University of Arizona, Tucson, AZ 85721-0088, USA.
authors.forename: Margarethakay
authors.initials: M
authors.lastname: Scavello
authors.affiliation: Department of Chemistry and Biochemistry, University of Arizona, Tucson, AZ 85721-0088, USA.
authors.forename: Alexandra R
authors.identifier: 0000-0002-9908-8457
authors.initials: AR
authors.lastname: Petlick
authors.affiliation: Department of Chemistry and Biochemistry, University of Arizona, Tucson, AZ 85721-0088, USA.
authors.forename: Ramya
authors.initials: R
authors.lastname: Ramesh
authors.affiliation: Department of Chemistry and Biochemistry, University of Arizona, Tucson, AZ 85721-0088, USA.
authors.forename: Valery F
authors.initials: VF
authors.lastname: Thompson
authors.affiliation: Department of Chemistry and Biochemistry, University of Arizona, Tucson, AZ 85721-0088, USA.
authors.forename: Pouya
authors.initials: P
authors.lastname: Lotfi
authors.affiliation: Department of Chemistry and Biochemistry, University of Arizona, Tucson, AZ 85721-0088, USA pcharest@email.arizona.edu.
authors.forename: Pascale G
authors.identifier: 0000-0002-2395-5294
authors.initials: PG
authors.lastname: Charest
mesh_terms: D000199:Actins / Q000378:metabolism; D002630:Chemotactic Factors / Q000494:pharmacology*; D002633:Chemotaxis; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D004023:Dictyostelium / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D000076225:Mechanistic Target of Rapamycin Complex 2 / Q000378:metabolism*; D008954:Models, Biological; D009218:Myosins / Q000378:metabolism; D010641:Phenotype; D015800:Protozoan Proteins / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D020827:rap1 GTP-Binding Proteins / Q000378:metabolism*; D018631:ras Proteins / Q000378:metabolism*
chemical_list: D000199:Actins; D002630:Chemotactic Factors; D015800:Protozoan Proteins; D000076225:Mechanistic Target of Rapamycin Complex 2; D017868:Cyclic AMP-Dependent Protein Kinases; D009218:Myosins; D020827:rap1 GTP-Binding Proteins; D018631:ras Proteins
keywords: Chemotactic signaling; Chemotaxis; Directional sensing; Migration; Negative feedback; PKA