Constitutively Active Gα16 Stimulates STAT3 via a c-Src/JAK- and ERK-dependent Mechanism
The hematopoietic-specific Gα16 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 Gα16 stimulates STAT3 in human embryonic kidney 293 cells. A const...
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Veröffentlicht in: | The Journal of biological chemistry 2003-12, Vol.278 (52), p.52154-52165 |
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Sprache: | eng |
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Zusammenfassung: | The hematopoietic-specific Gα16 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 Gα16 stimulates STAT3 in human embryonic kidney 293 cells. A constitutively active Gα16 mutant, Gα16QL, stimulated STAT3-dependent luciferase activity as well as the phosphorylation of STAT3 at both Tyr705 and Ser727. Gα16QL-induced STAT3 activation was enhanced by overexpression of extracellular signal-regulated kinase 1 (ERK1), but was inhibited by U0126, a Raf-1 inhibitor, and coexpression of the dominant negative mutants of Ras and Rac1. Inhibition of phospholipase Cβ, protein kinase C, and calmodulin-dependent kinase II by their respective inhibitors also suppressed Gα16QL-induced STAT3 activation. The involvement of tyrosine kinases such as c-Src and Janus kinase 2 and 3 (JAK2 and JAK3) in Gα16QL-induced activation of STAT3 was illustrated by the combined use of selective inhibitors and dominant negative mutants. In contrast, c-Jun N-terminal kinase, p38 MAPK, RhoA, Cdc42, phosphatidylinositol 3-kinase, and the epidermal growth factor receptor did not appear to be required. Similar observations were obtained with human erythroleukemia cells, where STAT3 phosphorylation was stimulated by C5a in a PTX-insensitive manner. Collectively, these results highlight the important regulatory roles of the Ras/Raf/MEK/ERK and c-Src/JAK pathways on the stimulation of STAT3 by activated Gα16. Demonstration of the involvement of different kinases in Gα16QL-induced STAT3 activation supports the involvement of multiple signaling pathways in the regulation of transcription by G proteins. |
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ISSN: | 0021-9258 1083-351X |
DOI: | 10.1074/jbc.M307299200 |