title: Thrombospondin 1 binding to calreticulin-LRP1 signals resistance to anoikis.
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.
authors.affiliation: Department of Pathology, VH 668 1530 3rd Ave., South, Birmingham, AL 35294-0019, USA.
authors.forename: Manuel A
authors.initials: MA
authors.lastname: Pallero
authors.forename: Carrie A
authors.initials: CA
authors.lastname: Elzie
authors.forename: Jiping
authors.initials: J
authors.lastname: Chen
authors.forename: Deane F
authors.initials: DF
authors.lastname: Mosher
authors.forename: Joanne E
authors.initials: JE
authors.lastname: Murphy-Ullrich
mesh_terms: D000818:Animals; D023102:Anoikis / Q000502:physiology*; D001665:Binding Sites / Q000502:physiology; D037282:Calreticulin / Q000819:agonists* / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D002448:Cell Adhesion / Q000187:drug effects / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D051379:Mice; D018345:Mice, Knockout; D010455:Peptides / Q000378:metabolism / Q000494:pharmacology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D017434:Protein Structure, Tertiary / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011973:Receptors, LDL / Q000819:agonists* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D019700:Thrombospondin 1 / Q000378:metabolism / Q000494:pharmacology*; D025521:Tumor Suppressor Proteins / Q000819:agonists* / Q000378:metabolism
chemical_list: D037282:Calreticulin; D053148:Caspase 3; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D010455:Peptides; D019869:Phosphatidylinositol 3-Kinases; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D051057:Proto-Oncogene Proteins c-akt; D011973:Receptors, LDL; D019700:Thrombospondin 1; D025521:Tumor Suppressor Proteins; C486645:Lrp1 protein, mouse; C499320:PARP1 protein, human; C499321:Parp1 protein, mouse; C505407:CASP3 protein, human; C505409:Casp3 protein, mouse