Mechanism of persistent protein kinase D1 translocation and activation.
The specificity of many signal transduction pathways relies on the spatiotemporal features of each signaling step. G protein-coupled receptor-mediated activation of protein kinases leads to diverse cellular effects. Upon receptor activation, PKD1 and several C-type protein kinases (PKCs), translocate to the plasma membrane and become catalytically active. Here we show that, unlike PKCs, PKD1 remains active at the membrane for hours. The two DAG binding C1 domains of PKD1 have distinct functional roles in targeting and maintaining PKD1 at the plasma membrane. C1A achieves fast, maximal, and reversible translocation, while C1B translocates partially, but persistently, to the plasma membrane. The persistent localization requires the C1B domain of PKD1, which binds Galphaq. We incorporate the kinetics of PKD1 translocation into a three-state model that suggests how PKD1 binding to DAG and Galphaq uniquely encodes frequency-dependent PKD1 signaling.
Oancea
Elena
E
HHMI, Children's Hospital, Harvard Medical School, 1309 Enders Building, 320 Longwood Avenue, Boston, MA 02115, USA.
Bezzerides
Vassilios J
VJ
Greka
Anna
A
Clapham
David E
DE
D002462:Cell Membrane / Q000201:enzymology*; D002478:Cells, Cultured; D018679:Cholinergic Agonists / Q000494:pharmacology; D004075:Diglycerides / Q000378:metabolism; D005057:Eukaryotic Cells / Q000201:enzymology*; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D019204:GTP-Binding Proteins / Q000378:metabolism*; D020962:Heterotrimeric GTP-Binding Proteins / Q000378:metabolism; D006728:Hormones / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D008954:Models, Biological; D009154:Mutation / Q000235:genetics; D011485:Protein Binding / Q000502:physiology; D020033:Protein Isoforms / Q000378:metabolism; D011493:Protein Kinase C / Q000235:genetics / Q000378:metabolism*; D017434:Protein Structure, Tertiary / Q000502:physiology; D021381:Protein Transport / Q000502:physiology*; D011930:Reaction Time / Q000187:drug effects / Q000235:genetics; D011956:Receptors, Cell Surface / Q000378:metabolism*; D011993:Recombinant Fusion Proteins; D015398:Signal Transduction / Q000502:physiology
D018679:Cholinergic Agonists; D004075:Diglycerides; D006728:Hormones; D020033:Protein Isoforms; D011956:Receptors, Cell Surface; D011993:Recombinant Fusion Proteins; C089212:protein kinase D; D011493:Protein Kinase C; D019204:GTP-Binding Proteins; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D020962:Heterotrimeric GTP-Binding Proteins