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Signal Transducer and Activator of Transcription 3 Activation by the -Opioid Receptor via G₁₄ Involves Multiple Intermediates

Department of Biochemistry, Molecular Neuroscience Center, and Biotechnology Research Institute, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China

The hematopoietic-specific G₁₄ links a variety of G protein-coupled receptors to phospholipase C (PLC) stimulation. Recent studies reveal that several G subunits are capable of activating signal transducer and activator of transcription (STAT) proteins. In the present study, we investigated the mechanism by which G₁₄ mediates receptor-induced stimulation of STAT3. In human embryonic kidney 293 cells, coexpression of G₁₄ with -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 G₁₄QL mutant also induced STAT3 phosphorylations at these sites and promoted STAT3-dependent luciferase activity. Requirements for PLC, protein kinase C (PKC), and calmodulin-dependent kinase II (CaMKII) in G₁₄QL-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 G₁₄QL, but no physical association between G₁₄QL and c-Src could be detected by coimmunoprecipitation. Various intermediates along the extracellular signal-regulated kinase signaling cascade were apparently required for G₁₄QL-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 G₁₄QL-induced responses. PLC, PKC, and CaMKII were shown to be involved in G₁₄QL-mediated c-Src phosphorylation. Similar results were obtained with human erythro-leukemia cells upon DPDPE treatment. These results demonstrate for the first time that G₁₄ activation can lead to STAT3 stimulation via a complex signaling network involving multiple intermediates.

Address correspondence to: Dr. Yung H. Wong, Department of Biochemistry, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China. E-mail: boyung{at}ust.hk

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