Sawasdikosol Sansana, Russo Kristin M, Burakoff Steven J
New York University Medical Center, Skirball Institute of Biomolecular Medicine, Department of Pathology, New York 10016, USA.
Blood. 2003 May 1;101(9):3687-9. doi: 10.1182/blood-2002-07-2316. Epub 2003 Jan 9.
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.
前列腺素E(2)（PGE(2)）是巨噬细胞在炎症部位释放的主要类花生酸产物。PGE(2)与其同源的7次跨膜G蛋白偶联受体（GPCRs）结合会激活信号通路，导致Fos转录因子的合成。由于Ste20丝氨酸/苏氨酸蛋白激酶（S/TPK）是酿酒酵母中G蛋白偶联信息素受体的关键信号转导分子，我们推测PGE(2) GPCRs可能激活Ste20的一种哺乳动物直系同源物。我们在此证明，造血细胞特异性的、与Ste20相关的S/TPK，即HPK1，其催化活性受到生理浓度PGE(2)的正向调节。此外，异位表达研究表明HPK1是PGE(2)诱导的fos基因转录的负调节因子。我们的数据表明，PGE(2)诱导的HPK1激活可能代表一种能够调节PGE(2)介导的基因转录的新型负调节途径。
