Modulating tissue responses to stress is an important therapeutic objective. Oxidative and genotoxic stresses caused by ionizing radiation are detrimental to healthy tissues but beneficial for treatment of cancer. CD47 is a signaling receptor for thrombospondin-1 and an attractive therapeutic target because blocking CD47 signaling protects normal tissues while sensitizing tumors to ionizing radiation. Here we utilized a metabolomic approach to define molecular mechanisms underlying this radioprotective activity. CD47-deficient cells and cd47-null mice exhibited global advantages in preserving metabolite levels after irradiation. Metabolic pathways required for controlling oxidative stress and mediating DNA repair were enhanced. Some cellular energetics pathways differed basally in CD47-deficient cells, and the global declines in the glycolytic and tricarboxylic acid cycle metabolites characteristic of normal cell and tissue responses to irradiation were prevented in the absence of CD47. Thus, CD47 mediates signaling from the extracellular matrix that coordinately regulates basal metabolism and cytoprotective responses to radiation injury. In contrast to structural elements of the extracellular matrix, matricellular proteins appear transiently during development and injury responses, but their sustained expression can contribute to chronic disease. Through interactions with other matrix components and specific cell surface receptors matricellular proteins regulate multiple signaling pathways, including those mediated by reactive oxygen and nitrogen species and H2S. Dysregulation of matricellular proteins contributes to the pathogenesis of vascular diseases and cancer. Defining the molecular mechanisms and receptors involved is revealing new therapeutic opportunities. Recent Advances: Thrombospondin-1 regulates NO, H2S, and superoxide production and signaling in several cell types. The thrombospondin-1 receptor CD47 plays a central role in inhibition of NO signaling, but other thrombospondin-1 receptors also modulate redox signaling. The matricellular protein CCN1 engages some of the same receptors to regulate redox signaling, and ADAMTS1 regulates NO signaling in Marfan syndrome. In addition to mediating matricellular protein signaling, redox signaling is emerging as an important pathway that controls the expression of several matricellular proteins. CRITICAL ISSUES: Redox signaling remains unexplored for many matricellular proteins. Their interactions with multiple cellular receptors remains an obstacle to defining signaling mechanisms, but improved transgenic models could overcome this barrier. FUTURE DIRECTIONS: Therapeutics targeting the TSP1 receptor CD47 may have beneficial effects for treating cardiovascular disease and cancer and have recently entered clinical trials. Biomarkers are needed to assess their effects on redox signaling in patients and to evaluate how these contribute to their therapeutic efficacy and potential side effects.
| Ramirez, Manuel U; Stirling, Elizabeth R; Emenaker, Nancy J et al. (2018) Thrombospondin-1 interactions regulate eicosanoid metabolism and signaling in cancer-related inflammation. Cancer Metastasis Rev : |
| Roberts, David D (2017) Extracellular Matrix and Redox Signaling in Cellular Responses to Stress. Antioxid Redox Signal 27:771-773 |
| Roberts, David D; Kaur, Sukhbir; Isenberg, Jeffrey S (2017) Regulation of cellular redox signaling by matricellular proteins in vascular biology, immunology, and cancer. Antioxid Redox Signal : |
| Miller, Thomas W; Soto-Pantoja, David R; Schwartz, Anthony L et al. (2015) CD47 Receptor Globally Regulates Metabolic Pathways That Control Resistance to Ionizing Radiation. J Biol Chem 290:24858-74 |
| Priya, Mani Krishna; Sahu, Giriraj; Soto-Pantoja, David R et al. (2015) Tipping off endothelial tubes: nitric oxide drives tip cells. Angiogenesis 18:175-89 |
| Thomas, Douglas D; Heinecke, Julie L; Ridnour, Lisa A et al. (2015) Signaling and stress: The redox landscape in NOS2 biology. Free Radic Biol Med 87:204-25 |
| Cook, Katherine L; Soto-Pantoja, David R; Abu-Asab, Mones et al. (2014) Mitochondria directly donate their membrane to form autophagosomes during a novel mechanism of parkin-associated mitophagy. Cell Biosci 4:16 |
| Rogers, Natasha M; Seeger, Franziska; Garcin, Elsa D et al. (2014) Regulation of soluble guanylate cyclase by matricellular thrombospondins: implications for blood flow. Front Physiol 5:134 |
| Navarathna, Dhammika H M L P; Munasinghe, Jeeva; Lizak, Martin J et al. (2013) MRI confirms loss of blood-brain barrier integrity in a mouse model of disseminated candidiasis. NMR Biomed 26:1125-34 |
| Soto-Pantoja, David R; Stein, Erica V; Rogers, Natasha M et al. (2013) Therapeutic opportunities for targeting the ubiquitous cell surface receptor CD47. Expert Opin Ther Targets 17:89-103 |
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