Signal Transducer and Activator of Transcription 3 Activation by the δ-Opioid Receptor via Gα14 Involves Multiple Intermediates
| Autor: | Rico K.H. Lo, Yung Hou Wong |
|---|---|
| Rok vydání: | 2004 |
| Předmět: |
STAT3 Transcription Factor
Transcriptional Activation rac1 GTP-Binding Protein Time Factors Phospholipase C beta Biology Mitogen-activated protein kinase kinase Transfection MAP2K7 CSK Tyrosine-Protein Kinase Phosphatidylinositol 3-Kinases Proto-Oncogene Proteins Receptors Opioid delta Ca2+/calmodulin-dependent protein kinase Humans ASK1 Cells Cultured Protein kinase C Pharmacology MAP kinase kinase kinase Cyclin-dependent kinase 2 Janus Kinase 2 Protein-Tyrosine Kinases Heterotrimeric GTP-Binding Proteins Molecular biology Cell biology DNA-Binding Proteins Isoenzymes src-Family Kinases Type C Phospholipases Mutation Trans-Activators ras Proteins biology.protein GTP-Binding Protein alpha Subunits Gq-G11 Molecular Medicine Cyclin-dependent kinase 9 Enkephalin D-Penicillamine (2 5) Signal Transduction |
| Zdroj: | Molecular Pharmacology. 65:1427-1439 |
| ISSN: | 1521-0111 0026-895X |
| Popis: | The hematopoietic-specific Galpha14 links a variety of G protein-coupled receptors to phospholipase Cbeta (PLCbeta) stimulation. Recent studies reveal that several Galpha subunits are capable of activating signal transducer and activator of transcription (STAT) proteins. In the present study, we investigated the mechanism by which Galpha14 mediates receptor-induced stimulation of STAT3. In human embryonic kidney 293 cells, coexpression of Galpha14 with delta-opioid receptor supported [D-Pen2, D-Pen5]enkephalin (DPDPE)-induced STAT3 phosphorylations at both Tyr705 and Ser727 in a pertussis toxin-insensitive manner. The constitutively active Galpha4QL mutant also induced STAT3 phosphorylations at these sites and promoted STAT3-dependent luciferase activity. Requirements for PLCbeta, protein kinase C (PKC), and calmodulin-dependent kinase II (CaMKII) in Galpha14QL-induced STAT3 activation were demonstrated by their respective inhibitors as well as by coexpression of their dominant-negative mutants. Inhibition of c-Src and Janus kinase 2 and 3 activities abolished STAT3 activation induced by Galpha14QL, but no physical association between Galpha14QL and c-Src could be detected by coimmunoprecipitation. Various intermediates along the extracellular signal-regulated kinase signaling cascade were apparently required for Galpha14QL-induced STAT3 activation; they included Ras/Rac1, Raf-1, and mitogen-activated protein kinase kinase-1/2. In contrast, functional blockade of c-Jun N-terminal kinase, p38 mitogen-activated protein kinase, and phosphatidylinositol-3 kinase had no effect on Galpha14QL-induced responses. PLCbeta, PKC, and CaMKII were shown to be involved in Galpha14QL-mediated c-Src phosphorylation. Similar results were obtained with human erythro-leukemia cells upon DPDPE treatment. These results demonstrate for the first time that Galpha14 activation can lead to STAT3 stimulation via a complex signaling network involving multiple intermediates. |
| Databáze: | OpenAIRE |
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