| Thrombospondin 1 binding to calreticulin-LRP1 signals resistance to anoikis. | |
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MedLine Citation:
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PMID: 18653767 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Anoikis, apoptotic cell death due to loss of cell adhesion, is critical for regulation of tissue homeostasis in tissue remodeling. Fibrogenesis is associated with reduced fibroblast apoptosis. The matricellular protein thrombospondin 1 (TSP1) regulates cell adhesion and motility during tissue remodeling and in fibrogenesis. The N-terminal domain of TSP1 binds to the calreticulin-LRP1 receptor co-complex to signal down-regulation of cell adhesion and increased cell motility through focal adhesion disassembly. TSP1 signaling through calreticulin-LRP1 activates cell survival signals such as PI3-kinase. Therefore, we tested the hypothesis that TSP1 supports cell survival under adhesion-independent conditions to facilitate tissue remodeling. Here, we show that platelet TSP1, its N-terminal domain (NoC1) as a recombinant protein, or a peptide comprising the calreticulin-LRP1 binding site [amino acids 17-35 (hep I)] in the N-terminal domain promotes fibroblast survival under anchorage-independent conditions. TSP1 activates Akt and decreases apoptotic signaling through caspase 3 and PARP1 in suspended fibroblasts. Inhibition of PI3K/Akt activity blocks TSP1-mediated anchorage-independent survival. Fibroblasts lacking LRP1 or expressing calreticulin lacking the TSP1 binding site do not respond to TSP1 with anchorage-independent survival. These data define a novel role for TSP1 signaling through the calreticulin/LRP1 co-complex in tissue remodeling and fibrotic responses through stimulation of anoikis resistance.-Pallero, M. A., Elzie, C. A., Chen, J., Mosher, D. F., Murphy-Ullrich, J. E. Thrombospondin 1 binding to calreticulin-LRP1 signals resistance to anoikis. |
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Authors:
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Manuel A Pallero; Carrie A Elzie; Jiping Chen; Deane F Mosher; Joanne E Murphy-Ullrich |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural Date: 2008-07-24 |
Journal Detail:
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Title: FASEB journal : official publication of the Federation of American Societies for Experimental Biology Volume: 22 ISSN: 1530-6860 ISO Abbreviation: FASEB J. Publication Date: 2008 Nov |
Date Detail:
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Created Date: 2008-10-31 Completed Date: 2008-11-18 Revised Date: 2012-02-15 |
Medline Journal Info:
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Nlm Unique ID: 8804484 Medline TA: FASEB J Country: United States |
Other Details:
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Languages: eng Pagination: 3968-79 Citation Subset: IM |
Affiliation:
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Department of Pathology, VH 668 1530 3rd Ave., South, Birmingham, AL 35294-0019, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Animals Anoikis / physiology* Binding Sites / physiology Calreticulin / agonists*, metabolism Caspase 3 / metabolism Cell Adhesion / drug effects, physiology Cell Survival / drug effects, physiology Fibroblasts / cytology, metabolism* Humans Mice Mice, Knockout Peptides / metabolism, pharmacology* Phosphatidylinositol 3-Kinases / metabolism Poly(ADP-ribose) Polymerases / metabolism Protein Structure, Tertiary / physiology Proto-Oncogene Proteins c-akt / metabolism Receptors, LDL / agonists*, metabolism Signal Transduction / drug effects*, physiology Thrombospondin 1 / metabolism, pharmacology* Tumor Suppressor Proteins / agonists*, metabolism |
| Grant Support | |
ID/Acronym/Agency:
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C06 RR 15490/RR/NCRR NIH HHS; HL079644/HL/NHLBI NIH HHS; T32AR47512-01A1/AR/NIAMS NIH HHS; T32DE014300/DE/NIDCR NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Calreticulin; 0/Lrp1 protein, mouse; 0/Peptides; 0/Receptors, LDL; 0/Thrombospondin 1; 0/Tumor Suppressor Proteins; EC 2.4.2.30/PARP1 protein, human; EC 2.4.2.30/Parp1 protein, mouse; EC 2.4.2.30/Poly(ADP-ribose) Polymerases; EC 2.7.1.-/Phosphatidylinositol 3-Kinases; EC 2.7.11.1/Proto-Oncogene Proteins c-akt; EC 3.4.22.-/CASP3 protein, human; EC 3.4.22.-/Casp3 protein, mouse; EC 3.4.22.-/Caspase 3 |
| Comments/Corrections | |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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