| SRC regulates TYR20 phosphorylation of transferrin receptor-1 and potentiates breast cancer cell survival. | |
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MedLine Citation:
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PMID: 21859709 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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Transferrin receptor 1 (TfR1) is a ubiquitous type II membrane receptor with 61aa 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 (ER+) MCF-7 cells lack caspase 3 and were not responsive to GA treatment. GA activated the three major signaling pathways of MAPK family, as well as caspase-3, 8, and PARP apoptotic pathway. Interestingly, only Src inhibitor PP2 significantly sensitized the cells to GA-mediated apoptosis. Further investigations by immunoprecipitation and confocal fluorescence microscopy revealed that Src and TfR1 are constitutively bound. Using TfR1-deficient Chinese hamster ovary (CHO) TRVB cells, point mutation studies showed that Tyr20 within the 20YTRF23 motif of the cytoplasmic region of TfR1 is the phosphorylation site by Src. TfR1 Tyr20 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 promotes breast cancer cell survival. |
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Authors:
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Jinlong Jian; Qing Yang; Xi Huang |
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Publication Detail:
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Type: JOURNAL ARTICLE Date: 2011-8-22 |
Journal Detail:
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Title: The Journal of biological chemistry Volume: - ISSN: 1083-351X ISO Abbreviation: - Publication Date: 2011 Aug |
Date Detail:
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Created Date: 2011-8-23 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 2985121R Medline TA: J Biol Chem Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Affiliation:
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NYU School of Medicine, United States; |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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