Hematopoietic progenitor kinase 1 (HPK1) negatively regulates prostaglandin E2-induced fos gene transcription.
Prostaglandin E(2) (PGE(2)) is the predominant eicosanoid product released by macrophages at the site of inflammation. Binding of PGE(2) to its cognate 7 transmembrane-spanning G protein-coupled receptors (GPCRs) activates signaling pathways, leading to the synthesis of the Fos transcription factor. Because the Ste20 serine/threonine protein kinase (S/TPK) is a critical signal transducer for the G protein-coupled pheromone receptor in Saccharomyces cerevisiae, we postulated that the PGE(2) GPCRs may activate one of the Ste20 mammalian orthologs. We demonstrate here that the catalytic activity of a hematopoietic cell-restricted, Ste20-related S/TPK, HPK1, is positively regulated by exposure to physiological concentrations of PGE(2). Furthermore, ectopic expression studies implicated HPK1 as a negative regulator of PGE(2)-induced transcription of the fos gene. Our data suggest that PGE(2)-induced activation of HPK1 may represent a novel negative regulatory pathway capable of modulating PGE(2)-mediated gene transcription.
Sawasdikosol
Sansana
S
New York University Medical Center, Skirball Institute of Biomolecular Medicine, Department of Pathology, New York 10016, USA. sawasdik@saturn.med.nyu.edu
Russo
Kristin M
KM
Burakoff
Steven J
SJ
D002384:Catalysis; D000242:Cyclic AMP / Q000494:pharmacology; D015232:Dinoprostone / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D017930:Genes, Reporter; D016762:Genes, fos; D006801:Humans; D019169:Jurkat Cells / Q000378:metabolism; D009363:Neoplasm Proteins / Q000187:drug effects / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D012333:RNA, Messenger / Q000096:biosynthesis; D018078:Receptors, Prostaglandin E / Q000187:drug effects / Q000378:metabolism; D058309:Receptors, Prostaglandin E, EP4 Subtype; D014158:Transcription, Genetic / Q000502:physiology*; D014162:Transfection
D009363:Neoplasm Proteins; C545650:PTGER4 protein, human; D012333:RNA, Messenger; D018078:Receptors, Prostaglandin E; D058309:Receptors, Prostaglandin E, EP4 Subtype; D000242:Cyclic AMP; C102102:hematopoietic progenitor kinase 1; D017346:Protein Serine-Threonine Kinases; D015232:Dinoprostone