Constitutively Active Gα16 Stimulates STAT3 via a c-Src/JAK- and ERK-dependent Mechanism

Abstract

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

Gene expression profiling in the leukemic stem cell-enriched CD34+ fraction identifies target genes that predict prognosis in normal karyotype AML

“…Although poorly understood, G15 a-subunit was shown to regulate cell differentiation and apoptosis through modulation of MAPKs 42 and transcription factors such as NF-kB, 43 and is capable of activating STAT3. 44 Interestingly, the expression of the third target gene UGP2 was recently shown to be upregulated by hypoxia in hepatocytes. 45 UGP2 was put forward as a potential target of hypoxia-inducible factors, which in turn are required for hematopoiesis 46,47 and hypothesized to be relevant in hematopoietic stem cell maintenance in hypoxic osteoblastic BM niches.…”

G16-mediated Activation of Nuclear Factor κB by the Adenosine A1 Receptor Involves c-Src, Protein Kinase C, and ERK Signaling

“…have previously established that activation of G 16 -coupled A1R leads to the stimulation of PLC␤ and Ca 2ϩ mobilization (22,27), and the subsequent activation of PKC and CaMKII is required for G␣ 16 -mediated stimulation of STAT3 (29). Thus, we examined if the PLC␤/PKC/CaMKII pathway is similarly required for G 16 -mediated stimulation of NFB.…”

“…8, B-E) clearly demonstrates the involvement of c-Src in G 16 -mediated stimulation of IKK/NFB by A1R. Although constitutively active G␣ 16 can activate c-Src in HEK 293 cells, the interaction is probably indirect because G␣ 16 does not directly associate with c-Src (29). It is interesting to note that in human epithelial cells, TNF-␣-induced cyclooxygenase-2 expression is mediated via c-Src/NFB in a PKC-dependent manner (43).…”

“…Stimulation of A1R by CHA can, nevertheless, lead to the activation and phosphorylation of JNK and p38 MAPK, and such activities can be effectively abolished by specific inhibitors of the two kinases. The requirement of Ras/Raf-1/MEK/ERK pathway, but not JNK or p38 MAPK, for G 16 -mediated activation of IKK/NFB is highly reminiscent of the regulation of STAT3 by G␣ 16 (29).…”

“…Because the constitutively active G␣ 16 QL can activate all three MAPKs in HEK 293 cells (29), we asked if the coupling of A1R to G␣ 16 can similarly stimulate the MAPKs. HEK 293 cells were transfected with A1R and G␣ 16 , treated with PTX, and then stimulated by CHA (10 M) for 10 min.…”