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PMID:18653767

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Citation

Pallero, MA, Elzie, CA, Chen, J, Mosher, DF and Murphy-Ullrich, JE (2008) Thrombospondin 1 binding to calreticulin-LRP1 signals resistance to anoikis. FASEB J. 22:3968-79

Abstract

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.

Links

PubMed PMC2574023 Online version:10.1096/fj.07-104802

Keywords

Animals; Anoikis/physiology; Binding Sites/physiology; Calreticulin/agonists; Calreticulin/metabolism; Caspase 3/metabolism; Cell Adhesion/drug effects; Cell Adhesion/physiology; Cell Survival/drug effects; Cell Survival/physiology; Fibroblasts/cytology; Fibroblasts/metabolism; Humans; Mice; Mice, Knockout; Peptides/metabolism; Peptides/pharmacology; Phosphatidylinositol 3-Kinases/metabolism; Poly(ADP-ribose) Polymerases/metabolism; Protein Structure, Tertiary/physiology; Proto-Oncogene Proteins c-akt/metabolism; Receptors, LDL/agonists; Receptors, LDL/metabolism; Signal Transduction/drug effects; Signal Transduction/physiology; Thrombospondin 1/metabolism; Thrombospondin 1/pharmacology; Tumor Suppressor Proteins/agonists; Tumor Suppressor Proteins/metabolism

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:TSP1

involved_in

GO:0043066: negative regulation of apoptotic process

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:TSP1

involved_in

GO:0051897: positive regulation of protein kinase B signaling

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:TSP1

involved_in

GO:0043154: negative regulation of cysteine-type endopeptidase activity involved in apoptotic process

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete


See also

References

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