Document Detail


Src regulates Tyr(20) phosphorylation of transferrin receptor-1 and potentiates breast cancer cell survival.
MedLine Citation:
PMID:  21859709     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Transferrin receptor 1 (TfR1) is a ubiquitous type II membrane receptor with 61 amino acids in the N-terminal cytoplasmic region. TfR1 is highly expressed in cancer cells, particularly under iron deficient conditions. Overexpression of TfR1 is thought to meet the increased requirement of iron uptake necessary for cell growth. In the present study, we used transferrin (Tf), a known ligand of TfR1, and gambogic acid (GA), an apoptosis-inducing agent and newly identified TfR1 ligand to investigate the signaling role of TfR1 in breast cancer cells. We found that GA but not Tf induced apoptosis in a TfR1-dependent manner in breast cancer MDA-MB-231 cells. Estrogen receptor-positive MCF-7 cells lack caspase-3 and were not responsive to GA treatment. GA activated the three major signaling pathways of the MAPK family, as well as caspase-3, -8, and Poly(ADP-ribose)polymerase apoptotic pathway. Interestingly, only Src inhibitor PP2 greatly sensitized the cells to GA-mediated apoptosis. Further investigations by confocal fluorescence microscopy and immunoprecipitation revealed that Src and TfR1 are constitutively bound. Using TfR1-deficient CHO TRVB cells, point mutation studies showed that Tyr(20) within the (20)YTRF(23) motif of the cytoplasmic region of TfR1 is the phosphorylation site by Src. TfR1 Tyr(20) phosphomutants were more sensitive to GA-mediated apoptosis. Our results indicate that, albeit its iron uptake function, TfR1 is a signaling molecule and tyrosine phosphorylation at position 20 by Src enhances anti-apoptosis and potentiates breast cancer cell survival.
Authors:
Jinlong Jian; Qing Yang; Xi Huang
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2011-08-22
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  286     ISSN:  1083-351X     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  2011 Oct 
Date Detail:
Created Date:  2011-10-10     Completed Date:  2011-12-12     Revised Date:  2013-06-27    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  35708-15     Citation Subset:  IM    
Affiliation:
Department of Medicine, New York University Cancer Institute, New York University School of Medicine, New York, New York 10016, USA.
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MeSH Terms
Descriptor/Qualifier:
Animals
Antigens, CD / genetics,  metabolism*
Apoptosis*
Breast Neoplasms / genetics,  metabolism*
CHO Cells
Caspase 3 / genetics,  metabolism
Cell Line, Tumor
Cell Survival / drug effects,  genetics
Cricetinae
Cricetulus
Female
Humans
MAP Kinase Signaling System*
Mitogen-Activated Protein Kinase Kinases / genetics
Neoplasm Proteins / agonists,  genetics,  metabolism*
Phosphorylation / drug effects,  genetics
Pyrimidines / pharmacology
Receptors, Transferrin / agonists,  genetics,  metabolism*
Xanthones / pharmacology
src-Family Kinases / genetics,  metabolism*
Grant Support
ID/Acronym/Agency:
CA16087/CA/NCI NIH HHS; CA34588/CA/NCI NIH HHS; ES00260/ES/NIEHS NIH HHS; R21 CA132684/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
0/AG 1879; 0/Antigens, CD; 0/CD71 antigen; 0/Neoplasm Proteins; 0/Pyrimidines; 0/Receptors, Transferrin; 0/Xanthones; 2752-65-0/gambogic acid; EC 2.7.10.2/src-Family Kinases; EC 2.7.12.2/Mitogen-Activated Protein Kinase Kinases; EC 3.4.22.-/CASP3 protein, human; EC 3.4.22.-/Caspase 3
Comments/Corrections

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