Abstract:
:Activation of phospholipase Cgamma1 (PLCgamma1) by vascular endothelial growth factor receptor-2 (VEGFR-2) in endothelial cells in part is responsible for angiogenesis in vivo. The cellular mechanisms exerting negative control over PLCgamma1 activation, however, remain unaddressed. Here by using in vitro and in vivo binding assays, we show that the Casitas B-lineage lymphoma (c-Cbl) E3 ubiquitin ligase constitutively associates with PLCgamma1 via its C-terminal domain and conditionally interacts with VEGFR-2 via the N-terminal/TKB domain. Site-directed mutagenesis of VEGFR-2 showed that full activation of c-Cbl requires its direct association with phospho-tyrosines 1052 and 1057 of VEGFR-2 via its TKB domain and indirect association with phospho-tyrosine 1173 of VEGFR-2 via PLCgamma1. The tertiary complex formation between VEGFR-2, PLCgamma1 and c-Cbl selectively promotes ubiquitylation and suppression of tyrosine phosphorylation of PLCgamma1 by a proteolysis-independent mechanism. Further analysis showed that association of c-Cbl with VEGFR-2 does not impact ubiquitylation, down-regulation, or tyrosine phosphorylation of VEGFR-2. Silencing of c-Cbl by siRNA revealed that endogenous c-Cbl plays an inhibitory role in angiogenesis. Our data demonstrate that corecruitment of c-Cbl and PLCgamma1 to VEGFR-2 serves as a mechanism to fine-tune the angiogenic signal relay of VEGFR-2.
journal_name
Proc Natl Acad Sci U S Aauthors
Singh AJ,Meyer RD,Navruzbekov G,Shelke R,Duan L,Band H,Leeman SE,Rahimi Ndoi
10.1073/pnas.0700809104subject
Has Abstractpub_date
2007-03-27 00:00:00pages
5413-8issue
13eissn
0027-8424issn
1091-6490pii
0700809104journal_volume
104pub_type
杂志文章abstract::A (Mg(2+) + Ca(2+))ATPase (ATP phosphohydrolase, EC 3.6.1.3) has been purified from sarcoplasmic reticulum using a single step centrifugation procedure. The preparation is >95% pure by weight and contains only 25-30% of the lipid associated with the enzyme in native sarcoplasmic reticulum. The purified enzyme is unabl...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.71.3.622
更新日期:1974-03-01 00:00:00
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journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.0404761101
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journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.80.24.7659
更新日期:1983-12-01 00:00:00
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journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.93.21.11534
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journal_title:Proceedings of the National Academy of Sciences of the United States of America
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journal_title:Proceedings of the National Academy of Sciences of the United States of America
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journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.84.9.2790
更新日期:1987-05-01 00:00:00
abstract::Injection of antisense oligonucleotides was used to investigate the function of c-mos in murine oocytes. Oocytes injected with antisense c-mos oligonucleotides completed the first meiotic division but failed to initiate meiosis II. Instead, loss of c-mos function led to chromosome decondensation, reformation of a nucl...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
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journal_title:Proceedings of the National Academy of Sciences of the United States of America
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更新日期:2001-10-09 00:00:00
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更新日期:2000-04-11 00:00:00
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journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.79.7.2186
更新日期:1982-04-01 00:00:00
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journal_title:Proceedings of the National Academy of Sciences of the United States of America
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journal_title:Proceedings of the National Academy of Sciences of the United States of America
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更新日期:2007-07-03 00:00:00
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journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.74.8.3485
更新日期:1977-08-01 00:00:00
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journal_title:Proceedings of the National Academy of Sciences of the United States of America
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doi:10.1073/pnas.79.10.3290
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journal_title:Proceedings of the National Academy of Sciences of the United States of America
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journal_title:Proceedings of the National Academy of Sciences of the United States of America
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更新日期:2008-04-29 00:00:00
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journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
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更新日期:2008-08-19 00:00:00
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journal_title:Proceedings of the National Academy of Sciences of the United States of America
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journal_title:Proceedings of the National Academy of Sciences of the United States of America
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journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
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更新日期:2014-08-12 00:00:00
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journal_title:Proceedings of the National Academy of Sciences of the United States of America
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doi:10.1073/pnas.81.17.5478
更新日期:1984-09-01 00:00:00
abstract::Organic hydroperoxide resistance (Ohr) enzymes are unique Cys-based, lipoyl-dependent peroxidases. Here, we investigated the involvement of Ohr in bacterial responses toward distinct hydroperoxides. In silico results indicated that fatty acid (but not cholesterol) hydroperoxides docked well into the active site of Ohr...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
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更新日期:2017-01-10 00:00:00