ZIA SC 009174 (ZIA) | |||
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Title | Roles of Glycoconjugates and Redox Signaling in Tumor Biology | ||
Institution | NCI, Bethesda, MD | ||
Principal Investigator | Roberts, David | NCI Program Director | N/A |
Cancer Activity | N/A | Division | CCR |
Funded Amount | $316,575 | Project Dates | 10/01/1988 - N/A |
Fiscal Year | 2011 | Project Type | Intramural |
Research Topics w/ Percent Relevance | Cancer Types w/ Percent Relevance | ||
Autoimmune Diseases (20.0%) Cancer (100.0%) Digestive Diseases (10.0%) Inflammatory Bowel Disease (10.0%) |
Breast (10.0%) Colon/Rectum (10.0%) Non Hodgkins Lymphoma (10.0%) Ovarian Cancer (10.0%) Vascular Disease (10.0%) |
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Research Type | |||
Cancer Progression and Metastasis Systemic Therapies - Discovery and Development |
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Abstract | |||
Amyloid-beta interacts with two cell surface receptors, CD36 and CD47, through which the matricellular protein thrombospondin-1 inhibits soluble guanylate cyclase activation. Here we examine whether amyloid-beta shares this inhibitory activity. Amyloid-beta inhibited both drug and nitric oxide-mediated activation of soluble guanylate cyclase in several cell types. Known cGMP-dependent functional responses to nitric oxide in platelets and vascular smooth muscle cells were correspondingly inhibited by amyloid-beta. Functional interaction of amyloid-beta with the scavenger receptor CD36 was indicated by inhibition of free fatty acid uptake via this receptor. Both soluble oligomer and fibrillar forms of amyloid-beta were active. In contrast, amyloid-beta did not compete with the known ligand SIRP-alpha for binding to CD47. However, both receptors were necessary for amyloid-beta to inhibit cGMP accumulation. These data suggest that amyloid-beta interaction with CD36 induces a CD47-dependent signal that inhibits soluble guanylate cyclase activation. Combined with the pleiotropic effects of inhibiting free fatty acid transport via CD36, these data provides a molecular mechanism through which amyloid-beta can contribute to the nitric oxide signaling deficiencies associated with Alzheimer's disease. Cell surface proteoglycans on T cells contribute to retroviral infection, binding of chemokines and other proteins, and are necessary for some T cell responses to the matricellular glycoprotein thrombospondin-1. The major cell surface proteoglycans expressed by primary T cells and Jurkat T cells have an apparent M(r) > 200,000 and are modified with chondroitin sulfate and heparan sulfate chains. Thrombospondin-1 bound in a heparin-inhibitable manner to this proteoglycan and to a soluble form released into the medium. Based on mass spectrometry, knockdown, and immunochemical analyses, the proteoglycan contains two major core proteins as follows: amyloid precursor-like protein-2 (APLP2, apparent M(r) 230,000) and CD47 (apparent M(r) > 250,000). CD47 is a known thrombospondin-1 receptor but was not previously reported to be a proteoglycan. This proteoglycan isoform of CD47 is widely expressed on vascular cells. Mutagenesis identified glycosaminoglycan modification of CD47 at Ser(64) and Ser(79). Inhibition of T cell receptor signaling by thrombospondin-1 was lost in CD47-deficient T cells that express the proteoglycan isoform of APLP2, indicating that binding to APLP2 is not sufficient. Inhibition of CD69 induction was restored in CD47-deficient cells by re-expressing CD47 or an S79A mutant but not by the S64A mutant. Therefore, inhibition of T cell receptor signaling by thrombospondin-1 is mediated by CD47 and requires its modification at Ser(64). |