期刊
JOURNAL OF CELL COMMUNICATION AND SIGNALING
卷 3, 期 3-4, 页码 337-347出版社
SPRINGER
DOI: 10.1007/s12079-009-0065-3
关键词
Angiogenesis; Cutis laxa; Elastic fibers; Fibulin; Fibronectin; Integrin; ROS; Thrombospondin; Tumor
类别
资金
- National Institutes of Health [HL071157, AG028048, CA118240]
- Welch Foundation
- American Heart Association South Central Affiliate
- EUNICE KENNEDY SHRIVER NATIONAL INSTITUTE OF CHILD HEALTH & HUMAN DEVELOPMENT [R01HD064824] Funding Source: NIH RePORTER
- NATIONAL CANCER INSTITUTE [R01CA118240] Funding Source: NIH RePORTER
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [R01HL071157] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE ON AGING [R01AG028048] Funding Source: NIH RePORTER
Interactions between the extracellular matrix (ECM) and cells are critical in embryonic development, tissue homeostasis, physiological remodeling, and tumorigenesis. Matricellular proteins, a group of ECM components, mediate cell-ECM interactions. One such molecule, Fibulin-5 is a 66-kDa glycoprotein secreted by various cell types, including vascular smooth muscle cells (SMCs), fibroblasts, and endothelial cells. Fibulin-5 contributes to the formation of elastic fibers by binding to structural components including tropoelastin and fibrillin-1, and to cross-linking enzymes, aiding elastic fiber assembly. Mice deficient in the fibulin-5 gene (Fbln5) exhibit systemic elastic fiber defects with manifestations of loose skin, tortuous aorta, emphysematous lung and genital prolapse. Although Fbln5 expression is down-regulated after birth, following the completion of elastic fiber formation, expression is reactivated upon tissue injury, affecting diverse cellular functions independent of its elastogenic function. Fibulin-5 contains an evolutionally conserved arginineglycine-aspartic acid (RGD) motif in the N-terminal region, which mediates binding to a subset of integrins, including alpha 5 beta 1, alpha v beta 3, and alpha v beta 5. Fibulin-5 enhances substrate attachment of endothelial cells, while inhibiting migration and proliferation in a cell type- and context-dependent manner. The antagonistic function of fibulin-5 in angiogenesis has been demonstrated in vitro and in vivo; fibulin-5 may block angiogenesis by inducing the anti-angiogenic molecule thrompospondin-1, by antagonizing VEGF(165)-mediated signaling, and/or by antagonizing fibronectin-mediated signaling through directly binding and blocking the alpha 5 beta 1 fibronectin receptor. The overall effect of fibulin-5 on tumor growth depends on the balance between the inhibitory property of fibulin-5 on angiogenesis and the direct effect of fibulin-5 on proliferation and migration of tumor cells. However, the effect of tumor-derived versus host microenvironment-derived fibulin-5 remains to be evaluated.
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