Cbl negatively regulates erythropoietin-induced growth and survival signaling through the proteasomal degradation of Src kinase

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URI http://shark.lib.kagawa-u.ac.jp/kuir/metadata/27638
Title
Cbl negatively regulates erythropoietin-induced growth and survival signaling through the proteasomal degradation of Src kinase
File
Description

Abstract

We examined the biological functions of the gene Cbl in erythropoietin (EPO) signaling using Cbl-deficient F-36P human erythroleukemia cells by the introduction of the Cbl siRNA expression vector. Knockdown of Cbl promoted EPO-dependent proliferation and survival of F-36P cells, especially at a low concentration of EPO (0.01U/mL), similar to serum concentrations of EPO in healthy volunteers (0.005-0.04U/mL). We found that Src was degraded mainly by the proteasomal pathway because the proteasome inhibitor MG-132 but not the lysosome inhibitor NH4Cl suppressed the EPO-induced degradation of Src in F-36P cells and that knockdown of Cbl inhibited EPO-induced ubiquitination and degradation of Src in F-36P cells. The experiments using the Src inhibitor PP1 and co-expression experiments further confirmed that Cbl and the kinase activity of Src are required for the EPO-induced ubiquitination of Src. In addition, the co-expression experiments and in vitro kinase assay demonstrated that the EPO-induced tyrosine phosphorylation and ubiquitination of Cbl were dependent on the kinase activity of Src but not Jak2. Thus, Cbl negatively regulates EPO signaling mainly through the proteasome-dependent degradation of Src, and the E3 ligase activity of Cbl and its tyrosine phosphorylation are regulated by Src but not Jak2.

KEYWORDS:

Cbl; Erythropoietin; Proteasome; Src; Ubiquitination

(医博甲599)

Author
著者 新谷 高理
著者(ヨミ) シンタニ タカミチ
著者(別表記) Shintani Takamichi
Publication Title
Blood Cells, Molecules and Diseases
Publication Title Alternative
Blood Cells Mol Dis
Volume
53
Issue
4
Start Page
211
End Page
218
Publisher
Academic Press
Elsevier
Published Date
2014-07-29
ISSN
1079-9796
NCID
AA11045786
PMID
25084697
DOI
10.1016/j.bcmd.2014.06.005
Resource Type
Thesis or Dissertation
Language
eng
Resource URL
https://doi.org/10.1016/j.bcmd.2014.06.005
Text Version
ETD
Grant ID
博甲第599号
Grant Date
2014-12-24
Degree Name
博士(医学)
Grantor
香川大学
Set
香川大学
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