Document Detail


Grb2 binding to Tyr284 in TbetaR-II is essential for mammary tumor growth and metastasis stimulated by TGF-beta.
MedLine Citation:
PMID:  18174260     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
We demonstrated previously that growth factor receptor-bound protein 2 (Grb2) associates with the transforming growth factor-beta (TGF-beta) type II receptor [TbetaR-II] upon its phosphorylation on Tyr284 by Src. Although this phosphotransferase reaction is critical in mediating TGF-beta stimulation of epithelial-mesenchymal transition (EMT) and invasion in mammary epithelial cells (MECs), the necessity of Grb2 in promoting these TGF-beta-dependent events remain purely correlative. Herein, we further evaluated the role of Grb2 in mediating the oncogenic activities of TGF-beta and show that the binding of Grb2 to TbetaR-II paralleled the induction of EMT in MECs stimulated by TGF-beta. Introducing siRNAs against Grb2 or expression of a TbetaR-II mutant that cannot bind Grb2 (i.e. Y284F-TbetaR-II) had no effect on the ability of TGF-beta to activate Smad3, but significantly impaired its stimulation of p38 mitogen-activated protein kinase (MAPK) in MECs. Importantly, these same cellular conditions also prevented the ability of MECs to undergo EMT in response to TGF-beta, and to invade synthetic basement membranes when stimulated by beta3 integrin and TGF-beta. Finally, we show that the ability of TGF-beta to stimulate breast cancer growth and pulmonary metastasis in mice required TbetaR-II to be phosphorylated on Tyr284, which activated p38 MAPK in developing and progressing mammary tumors. Collectively, our findings have established the necessity of Grb2 in mediating TGF-beta stimulation of EMT and invasion in MECs, as well as demonstrated the essential function of the alphavbeta3 integrin:Src:phospho-Y284-TbetaR-II:Grb2:p38 MAPK signaling axis to promote breast cancer growth and metastasis in vivo.
Authors:
Amy J Galliher-Beckley; William P Schiemann
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2008-01-03
Journal Detail:
Title:  Carcinogenesis     Volume:  29     ISSN:  1460-2180     ISO Abbreviation:  Carcinogenesis     Publication Date:  2008 Feb 
Date Detail:
Created Date:  2008-03-03     Completed Date:  2008-03-25     Revised Date:  2014-09-12    
Medline Journal Info:
Nlm Unique ID:  8008055     Medline TA:  Carcinogenesis     Country:  England    
Other Details:
Languages:  eng     Pagination:  244-51     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Animals
Cell Proliferation
Female
GRB2 Adaptor Protein / chemistry,  physiology*
Humans
MAP Kinase Signaling System
Mammary Neoplasms, Animal / metabolism*
Mice
Mice, Inbred BALB C
Neoplasm Metastasis
Neoplasm Transplantation
Phosphotransferases / metabolism
Protein-Serine-Threonine Kinases / chemistry,  physiology*
Receptors, Transforming Growth Factor beta / chemistry,  physiology*
Transforming Growth Factor beta / metabolism*
Tyrosine / chemistry*
src-Family Kinases / metabolism
Grant Support
ID/Acronym/Agency:
CA095519/CA/NCI NIH HHS; CA129359/CA/NCI NIH HHS; R01 CA095519/CA/NCI NIH HHS; R01 CA095519-06/CA/NCI NIH HHS; R01 CA129359/CA/NCI NIH HHS; R01 CA129359-01/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
0/GRB2 Adaptor Protein; 0/Receptors, Transforming Growth Factor beta; 0/Transforming Growth Factor beta; 42HK56048U/Tyrosine; EC 2.7.-/Phosphotransferases; EC 2.7.10.2/src-Family Kinases; EC 2.7.11.1/Protein-Serine-Threonine Kinases; EC 2.7.11.30/transforming growth factor-beta type II receptor
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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