Prostacyclin receptor induces STAT1 and STAT3 phosphorylations in human erythroleukemia cells: a mechanism requiring PTX-insensitive G proteins, ERK and JNK.
The ability of the human prostacyclin receptor (hIP) to regulate the activities of signal transducers and activators of transcription (STATs) has not yet been documented. In the present study, we have delineated the mechanism by which hIP induces STAT3 phosphorylations in human erythroleukemia (HEL) cells. Stimulation of endogenous hIP by its specific agonist, cicaprost, resulted in STAT3 Tyr705 and Ser727 phosphorylations in a time- and concentration-dependent manner. Cicaprost-induced STAT3 Tyr705 and Ser727 phosphorylations were resistant to pertussis toxin (PTX) treatment, suggesting that these responses were mediated through PTX-insensitive G proteins. In addition, extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK), but not p38 MAPK, were shown to be phosphorylated by cicaprost in a time- and concentration-dependent manner via PTX-insensitive G proteins. The levels of the interaction between STAT3, ERK and JNK were enhanced by cicaprost treatment. The involvement of Raf-1, MEK1/2 and JNK in cicaprost-induced phosphorylations of STAT3 was illustrated by the use of their selective inhibitors. In contrast, p38 MAPK did not appear to be required. Similar observations were obtained with STAT1 upon stimulation by cicaprost. Taken together, these results demonstrate for the first time that hIP activation by cicaprost can lead to STAT1 and STAT3 phosphorylations via signaling pathways involving PTX-insensitive G proteins, ERK and JNK.
Department of Biochemistry, Molecular Neuroscience Center, and Biotechnology Research Institute, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China.
Rico K H
RK
Lo
Helen
H
Wise
Yung H
YH
Wong
D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D011464:Epoprostenol / Q000031:analogs & derivatives / Q000494:pharmacology / Q000502:physiology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000502:physiology*; D019204:GTP-Binding Proteins / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D004915:Leukemia, Erythroblastic, Acute / Q000378:metabolism*; D048369:MAP Kinase Kinase 1 / Q000502:physiology; D048670:MAP Kinase Kinase 4 / Q000502:physiology*; D020930:MAP Kinase Kinase Kinases / Q000502:physiology; D037342:Pertussis Toxin / Q000494:pharmacology; D010766:Phosphorylation; D011518:Proto-Oncogene Proteins / Q000502:physiology; D019908:Proto-Oncogene Proteins c-raf / Q000502:physiology; D044006:Receptors, Epoprostenol / Q000819:agonists / Q000502:physiology*; D050794:STAT1 Transcription Factor / Q000737:chemistry / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000737:chemistry / Q000378:metabolism*; D012694:Serine / Q000032:analysis; D015398:Signal Transduction / Q000502:physiology; D013997:Time Factors; D014158:Transcription, Genetic; D014443:Tyrosine / Q000032:analysis
D011518:Proto-Oncogene Proteins; D044006:Receptors, Epoprostenol; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D014443:Tyrosine; D012694:Serine; D011464:Epoprostenol; D037342:Pertussis Toxin; D019908:Proto-Oncogene Proteins c-raf; D048049:Extracellular Signal-Regulated MAP Kinases; D020930:MAP Kinase Kinase Kinases; C069937:MAP3K8 protein, human; D048369:MAP Kinase Kinase 1; D048670:MAP Kinase Kinase 4; D019204:GTP-Binding Proteins; C043867:cicaprost