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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

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.

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

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