TY - JOUR
T1 - The JAK-inhibitor, JAB/SOCS-1 selectively inhibits, cytokine-induced, but not v-Src induced JAK-STAT activation
AU - Iwamoto, Takashi
AU - Senga, Takeshi
AU - Naito, Yuko
AU - Matsuda, Satoru
AU - Miyake, Yozo
AU - Yoshimura, Akihiko
AU - Hamaguchi, Michinari
N1 - Funding Information:
We thank Dr Toshio Hirano for STAT3 plasmid and Dr Izumi Nakashima for critical reading of the manuscript. IL-6 is a gift from Kirin Brewer Co. Ltd. This work was supported by grant-in-aids for COE Research from the Ministry of Education, Science and Culture of Japan and for Scientific Research of Japan Society for Promotion of Science.
PY - 2000/9/28
Y1 - 2000/9/28
N2 - Recently, constitutive activation of JAK kinases (JAKs) and/or signal transducers and activators of transcription (STATs) has been reported in growing numbers of human cancer cells as well as oncogene-transformed cells. JAB/SOCS-1 has been shown to be an intrinsic JAK tyrosine kinase inhibitor and to suppress the cytokine-dependent JAK-STAT pathway. In this report, we investigated the effect of ectopic expression of JAB on v-Src-induced JAK-STAT activation. Forced expression of JAB in v-Src-transformed NIH3T3 cells neither suppressed phosphorylation of STAT3 and JAK1/JAK2 nor blocked STAT3-reporter gene activation. Colony forming assay also showed that JAB did not suppress v-Src-lnduced transformation of NIH3T3 cells, while dominant negative STAT3 suppressed it. In contrast, JAB could downregulate pbospborylation of STAT1 and STAT3 induced by interferon gamma (IFN(γ)) and interleukin-6 (IL-6) plus soluble IL6 receptor (sIL-6R), respectively. Furthermore, in vitro kinase assay indicated that JAB suppressed byperactivation of JAK1/JAK2 and JAK1 induced by INF(γ) and IL-6 plus sIL-6R respectively, but not v-Src-induced basal JAKI/JAK2 activity. Nevertheless, both JAK1/JAK2 activated by v-Src and that activated by IL-6 plus slL-6R could similarly bind JAB. These results clearly demonstrate that JAB distinguishes cytokine-induced JAK-STAT signaling from v-Src-induced one and can not suppress the transformation with v-Src.
AB - Recently, constitutive activation of JAK kinases (JAKs) and/or signal transducers and activators of transcription (STATs) has been reported in growing numbers of human cancer cells as well as oncogene-transformed cells. JAB/SOCS-1 has been shown to be an intrinsic JAK tyrosine kinase inhibitor and to suppress the cytokine-dependent JAK-STAT pathway. In this report, we investigated the effect of ectopic expression of JAB on v-Src-induced JAK-STAT activation. Forced expression of JAB in v-Src-transformed NIH3T3 cells neither suppressed phosphorylation of STAT3 and JAK1/JAK2 nor blocked STAT3-reporter gene activation. Colony forming assay also showed that JAB did not suppress v-Src-lnduced transformation of NIH3T3 cells, while dominant negative STAT3 suppressed it. In contrast, JAB could downregulate pbospborylation of STAT1 and STAT3 induced by interferon gamma (IFN(γ)) and interleukin-6 (IL-6) plus soluble IL6 receptor (sIL-6R), respectively. Furthermore, in vitro kinase assay indicated that JAB suppressed byperactivation of JAK1/JAK2 and JAK1 induced by INF(γ) and IL-6 plus sIL-6R respectively, but not v-Src-induced basal JAKI/JAK2 activity. Nevertheless, both JAK1/JAK2 activated by v-Src and that activated by IL-6 plus slL-6R could similarly bind JAB. These results clearly demonstrate that JAB distinguishes cytokine-induced JAK-STAT signaling from v-Src-induced one and can not suppress the transformation with v-Src.
KW - Cytokine
KW - JAB
KW - JAK
KW - STAT
KW - Src
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U2 - 10.1038/sj.onc.1203829
DO - 10.1038/sj.onc.1203829
M3 - Article
C2 - 11032030
AN - SCOPUS:0034726958
SN - 0950-9232
VL - 19
SP - 4795
EP - 4801
JO - Oncogene
JF - Oncogene
IS - 41
ER -
