| RRC ID |
19641
|
| 著者 |
Fukumoto T, Kubota Y, Kitanaka A, Yamaoka G, Ohara-Waki F, Imataki O, Ohnishi H, Ishida T, Tanaka T.
|
| タイトル |
Gab1 transduces PI3K-mediated erythropoietin signals to the Erk pathway and regulates erythropoietin-dependent proliferation and survival of erythroid cells.
|
| ジャーナル |
Cell Signal
|
| Abstract |
In this study, we examined the biological functions of Gab1 in erythropoietin receptor (EPOR)-mediated signaling in vivo. Knockdown of Gab1 by the introduction of the Gab1 siRNA expression vector into F-36P human erythroleukemia (F-36P-Gab1-siRNA) cells resulted in a reduction of cell proliferation and survival in response to EPO. EPO-induced activation of Erk1/2 but not of Akt was significantly suppressed in F-36P-Gab1-siRNA cells compared with mock-transfected F-36P cells. The co-immunoprecipitation experiments revealed an EPO-enhanced association of Gab1 with the Grb2-SOS1 complex and SHP-2 in F-36P cells. A selective inhibitor of phosphatidylinositol 3-kinase (PI3K) LY294002 and short interfering RNA (siRNA) duplexes targeting the p85 regulatory subunit of PI3K (p85-siRNA) independently suppressed tyrosine phosphorylation of Gab1; its association with Grb2, SHP-2 and p85; and the activation of Erk in EPO-treated F-36P cells. LY294002 inhibited EPO-induced tyrosine phosphorylation of Gab1 and its association with Grb2 in human primary EPO-sensitive erythroid cells. The co-immunoprecipitation experiments using the Jak inhibitor AG490 or siRNA duplexes targeting Jak2 and in vitro binding experiments demonstrated that Jak2 regulated Gab1-mediated Erk activation through tyrosine phosphorylation of Gab1. Taken together, these results suggest that Gab1 couples PI3K-mediated EPO signals with the Ras/Erk pathway and that Gab1 plays an important role in EPOR-mediated signal transduction involved in the proliferation and survival of erythroid cells.
|
| 巻・号 |
21(12)
|
| ページ |
1775-83
|
| 公開日 |
2009-12-1
|
| DOI |
10.1016/j.cellsig.2009.07.013
|
| PII |
S0898-6568(09)00220-4
|
| PMID |
19665053
|
| MeSH |
Adaptor Proteins, Signal Transducing / genetics
Adaptor Proteins, Signal Transducing / metabolism*
Apoptosis
Cell Line, Tumor
Cell Proliferation
Chromones / pharmacology
Enzyme Inhibitors / pharmacology
Erythroid Cells / cytology*
Erythroid Cells / metabolism
Erythropoietin / metabolism*
GRB2 Adaptor Protein / metabolism
Gene Knockdown Techniques
Humans
Janus Kinase 2 / antagonists & inhibitors
Janus Kinase 2 / metabolism
Leukemia, Erythroblastic, Acute / metabolism
Mitogen-Activated Protein Kinase 1 / metabolism*
Mitogen-Activated Protein Kinase 3 / metabolism*
Morpholines / pharmacology
Phosphatidylinositol 3-Kinases / metabolism*
Protein Tyrosine Phosphatase, Non-Receptor Type 11 / metabolism
Receptors, Erythropoietin / metabolism
SOS1 Protein / metabolism
|
| IF |
3.968
|
| 引用数 |
8
|
|
WOS 分野
|
CELL BIOLOGY
|
| リソース情報 |
| ヒト・動物細胞 |
F-36P(RCB0775) |
