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The hematopoietic-specific G␣ 16 protein has recently been shown to mediate receptor-induced activation of the signal transducer and activator of transcription 3 (STAT3). In the present study, we have delineated the mechanism by which G␣ 16

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The hematopoietic-specific G␣ 14 links a variety of G proteincoupled 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 G␣ 14 mediates receptor-induced stimulation of STAT3. In human embryonic kidney 293 cells, coexpression of G␣ 14 with ␦-opioid receptor supported [D-Pen 2 ,]enkephalin (DPDPE)-induced STAT3 phosphorylations at both Tyr 705 and Ser 727 in a pertussis toxin-insensitive manner. The constitutively active G␣ 14 QL 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 G␣ 14 QL-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 G␣ 14 QL, but no physical association between G␣ 14 QL and c-Src could be detected by coimmunoprecipitation. Various intermediates along the extracellular signal-regulated kinase signaling cascade were apparently required for G␣ 14 QL-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 G␣ 14 QL-induced responses. PLC␤, PKC, and CaMKII were shown to be involved in G␣ 14 QL-mediated c-Src phosphorylation. Similar results were obtained with human erythroleukemia cells upon DPDPE treatment. These results demonstrate for the first time that G␣ 14 activation can lead to STAT3 stimulation via a complex signaling network involving multiple intermediates.

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