title: Arrestins function in cAR1 GPCR-mediated signaling and cAR1 internalization in the development of Dictyostelium discoideum.
abstract: Oscillation of chemical signals is a common biological phenomenon, but its regulation is poorly understood. At the aggregation stage of Dictyostelium discoideum development, the chemoattractant cAMP is synthesized and released at 6-min intervals, directing cell migration. Although the G protein-coupled cAMP receptor cAR1 and ERK2 are both implicated in regulating the oscillation, the signaling circuit remains unknown. Here we report that D. discoideum arrestins regulate the frequency of cAMP oscillation and may link cAR1 signaling to oscillatory ERK2 activity. Cells lacking arrestins (adcB(-)C(-)) display cAMP oscillations during the aggregation stage that are twice as frequent as for wild- type cells. The adcB(-)C(-) cells also have a shorter period of transient ERK2 activity and precociously reactivate ERK2 in response to cAMP stimulation. We show that arrestin domain-containing protein C (AdcC) associates with ERK2 and that activation of cAR1 promotes the transient membrane recruitment of AdcC and interaction with cAR1, indicating that arrestins function in cAR1-controlled periodic ERK2 activation and oscillatory cAMP signaling in the aggregation stage of D. discoideum development. In addition, ligand-induced cAR1 internalization is compromised in adcB(-)C(-) cells, suggesting that arrestins are involved in elimination of high-affinity cAR1 receptors from cell surface after the aggregation stage of multicellular development.
authors.affiliation: Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
authors.forename: Xiumei
authors.initials: X
authors.lastname: Cao
authors.affiliation: Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China Chemotaxis Signal Section, Laboratory of Immunogenetics, National Institutes of Health, Rockville, MD 20852 tjin@niaid.nih.gov yanjianshe@sjtu.edu.cn.
authors.forename: Jianshe
authors.initials: J
authors.lastname: Yan
authors.affiliation: Laboratory of Cell Biology, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892.
authors.forename: Shi
authors.initials: S
authors.lastname: Shu
authors.affiliation: Laboratory of Immunogenetics Imaging Facility, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD 20852.
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Brzostowski
authors.affiliation: Chemotaxis Signal Section, Laboratory of Immunogenetics, National Institutes of Health, Rockville, MD 20852 tjin@niaid.nih.gov yanjianshe@sjtu.edu.cn.
authors.forename: Tian
authors.initials: T
authors.lastname: Jin
mesh_terms: D019390:Arrestins / Q000378:metabolism*; D004023:Dictyostelium / Q000254:growth & development* / Q000378:metabolism; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D010766:Phosphorylation; D011953:Receptors, Cyclic AMP / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D019390:Arrestins; D011953:Receptors, Cyclic AMP; D043562:Receptors, G-Protein-Coupled; D019950:Mitogen-Activated Protein Kinase 1