Thrombospondin 1 binding to calreticulin-LRP1 signals resistance to anoikis

Manuel A. Pallero, Carrie A Elzie, Jiping Chen, Deane F. Mosher, Joanne E. Murphy-Ullrich

Research output: Contribution to journalArticle

54 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)3968-3979
Number of pages12
JournalFASEB Journal
Volume22
Issue number11
DOIs
StatePublished - Nov 1 2008

Fingerprint

Anoikis
Calreticulin
Thrombospondin 1
Fibroblasts
Cell adhesion
Cell Adhesion
Tissue
Phosphatidylinositol 3-Kinases
Cell Movement
Tissue homeostasis
Cell Survival
Adhesion
Binding Sites
Cells
Focal Adhesions
Cell death
Platelets
Recombinant Proteins
Caspase 3
Homeostasis

Keywords

  • Akt
  • Apoptosis
  • Cell adhesion
  • Fibroblasts
  • Focal adhesions

ASJC Scopus subject areas

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

Cite this

Pallero, M. A., Elzie, C. A., Chen, J., Mosher, D. F., & Murphy-Ullrich, J. E. (2008). Thrombospondin 1 binding to calreticulin-LRP1 signals resistance to anoikis. FASEB Journal, 22(11), 3968-3979. https://doi.org/10.1096/fj.07-104802

Thrombospondin 1 binding to calreticulin-LRP1 signals resistance to anoikis. / Pallero, Manuel A.; Elzie, Carrie A; Chen, Jiping; Mosher, Deane F.; Murphy-Ullrich, Joanne E.

In: FASEB Journal, Vol. 22, No. 11, 01.11.2008, p. 3968-3979.

Research output: Contribution to journalArticle

Pallero, MA, Elzie, CA, Chen, J, Mosher, DF & Murphy-Ullrich, JE 2008, 'Thrombospondin 1 binding to calreticulin-LRP1 signals resistance to anoikis', FASEB Journal, vol. 22, no. 11, pp. 3968-3979. https://doi.org/10.1096/fj.07-104802
Pallero MA, Elzie CA, Chen J, Mosher DF, Murphy-Ullrich JE. Thrombospondin 1 binding to calreticulin-LRP1 signals resistance to anoikis. FASEB Journal. 2008 Nov 1;22(11):3968-3979. https://doi.org/10.1096/fj.07-104802
Pallero, Manuel A. ; Elzie, Carrie A ; Chen, Jiping ; Mosher, Deane F. ; Murphy-Ullrich, Joanne E. / Thrombospondin 1 binding to calreticulin-LRP1 signals resistance to anoikis. In: FASEB Journal. 2008 ; Vol. 22, No. 11. pp. 3968-3979.
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