Abstract:
:The Src homology 2-containing phosphotyrosine phosphatase (SHP2) is primarily a positive effector of receptor tyrosine kinase signaling. However, the molecular mechanism by which SHP2 effects its biological function is unknown. In this report, we provide evidence that defines the molecular mechanism and site of action of SHP2 in the epidermal growth factor-induced mitogenic pathway. We demonstrate that SHP2 acts upstream of Ras and functions by increasing the half-life of activated Ras (GTP-Ras) in the cell by interfering with the process of Ras inactivation catalyzed by Ras GTPase-activating protein (RasGAP). It does so by inhibition of tyrosine phosphorylation-dependent translocation of RasGAP to the plasma membrane, to its substrate (GTP-Ras) microdomain. Inhibition is achieved through the dephosphorylation of RasGAP binding sites at the level of the plasma membrane. We have identified Tyr992 of the epidermal growth factor receptor (EGFR) to be one such site, since its mutation to Phe renders the EGFR refractory to the effect of dominant-negative SHP2. To our knowledge, this is the first report to outline the site and molecular mechanism of action of SHP2 in EGFR signaling, which may also serve as a model to describe its role in other receptor tyrosine kinase signaling pathways.
journal_name
Mol Cell Bioljournal_title
Molecular and cellular biologyauthors
Agazie YM,Hayman MJdoi
10.1128/mcb.23.21.7875-7886.2003subject
Has Abstractpub_date
2003-11-01 00:00:00pages
7875-86issue
21eissn
0270-7306issn
1098-5549journal_volume
23pub_type
杂志文章abstract::In Saccharomyces cerevisiae, the MET25 gene encodes O-acetylhomoserine sulfhydrylase. Synthesis of this enzyme is repressed by the presence of S-adenosylmethionine (AdoMet) in the growth medium. We identified cis elements required for MET25 expression by analyzing small deletions in the MET25 promoter region. The resu...
journal_title:Molecular and cellular biology
pub_type: 杂志文章
doi:10.1128/mcb.9.8.3292
更新日期:1989-08-01 00:00:00
abstract::Oncostatin M is a polypeptide cytokine, produced by normal and malignant hematopoietic cells, that has several in vitro activities, including the ability to inhibit growth of cultured carcinoma cells. Here we present a structural and functional comparison of two oncostatin M-related proteins (Mr 36,000 and 32,000) sec...
journal_title:Molecular and cellular biology
pub_type: 杂志文章
doi:10.1128/mcb.10.5.1882
更新日期:1990-05-01 00:00:00
abstract::The 3' noncoding region element (AUUUA)n specifically targets many short-lived mRNAs for degradation. Although the mechanism by which this sequence functions is not yet understood, a potential link between facilitated mRNA turnover and translation has been implied by the stabilization of cellular mRNAs in the presence...
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pub_type: 杂志文章
doi:10.1128/mcb.13.3.1971
更新日期:1993-03-01 00:00:00
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pub_type: 杂志文章,评审
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更新日期:2014-04-01 00:00:00
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journal_title:Molecular and cellular biology
pub_type: 杂志文章
doi:10.1128/mcb.17.2.571
更新日期:1997-02-01 00:00:00
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journal_title:Molecular and cellular biology
pub_type: 杂志文章
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journal_title:Molecular and cellular biology
pub_type: 杂志文章
doi:10.1128/mcb.16.5.1936
更新日期:1996-05-01 00:00:00
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journal_title:Molecular and cellular biology
pub_type: 杂志文章
doi:10.1128/mcb.3.4.570
更新日期:1983-04-01 00:00:00
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pub_type: 杂志文章
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pub_type: 杂志文章
doi:10.1128/mcb.13.11.7006
更新日期:1993-11-01 00:00:00
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journal_title:Molecular and cellular biology
pub_type: 杂志文章
doi:10.1128/mcb.18.12.7030
更新日期:1998-12-01 00:00:00
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pub_type: 杂志文章
doi:10.1128/mcb.20.8.2874-2879.2000
更新日期:2000-04-01 00:00:00
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journal_title:Molecular and cellular biology
pub_type: 杂志文章
doi:10.1128/mcb.17.3.1731
更新日期:1997-03-01 00:00:00
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pub_type: 杂志文章
doi:10.1128/MCB.25.9.3648-3657.2005
更新日期:2005-05-01 00:00:00
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journal_title:Molecular and cellular biology
pub_type: 杂志文章
doi:10.1128/mcb.2.9.1134
更新日期:1982-09-01 00:00:00
abstract::Progression through mitosis requires the inactivation of the protein kinase activity of the p34cdc2-cyclin complex by a mechanism involving the degradation of cyclin. We have examined the stability in Xenopus egg extracts of radiolabeled Xenopus or sea urchin B-type cyclins synthesized in reticulocyte lysates. Xenopus...
journal_title:Molecular and cellular biology
pub_type: 杂志文章
doi:10.1128/mcb.13.3.1480
更新日期:1993-03-01 00:00:00
abstract::Chemical carcinogenesis in mouse skin has been useful in delineating the molecular events that underlie squamous cell carcinoma progression. A late event in this progression, the epithelial-to-mesenchymal transition (EMT), is characterized by the loss of epithelial markers and the presence of mesenchymal markers. One ...
journal_title:Molecular and cellular biology
pub_type: 杂志文章
doi:10.1128/MCB.21.16.5478-5487.2001
更新日期:2001-08-01 00:00:00
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journal_title:Molecular and cellular biology
pub_type: 杂志文章
doi:10.1128/mcb.9.10.4337
更新日期:1989-10-01 00:00:00
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更新日期:2009-05-01 00:00:00
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journal_title:Molecular and cellular biology
pub_type: 杂志文章
doi:10.1128/mcb.7.12.4204
更新日期:1987-12-01 00:00:00
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pub_type: 杂志文章
doi:10.1128/mcb.8.7.2942
更新日期:1988-07-01 00:00:00
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journal_title:Molecular and cellular biology
pub_type: 杂志文章
doi:10.1128/mcb.12.1.22
更新日期:1992-01-01 00:00:00
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更新日期:1997-04-01 00:00:00
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pub_type: 杂志文章
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更新日期:1993-03-01 00:00:00
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pub_type: 杂志文章
doi:10.1128/mcb.13.9.5245
更新日期:1993-09-01 00:00:00
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journal_title:Molecular and cellular biology
pub_type: 杂志文章
doi:10.1128/mcb.7.2.887
更新日期:1987-02-01 00:00:00
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pub_type: 杂志文章
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更新日期:1996-03-01 00:00:00