期刊
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE
卷 1865, 期 6, 页码 1516-1524出版社
ELSEVIER SCIENCE BV
DOI: 10.1016/j.bbadis.2019.03.001
关键词
Platelet-derived growth factor receptors; Cadherin-11; Proliferation; Fibroblasts; Glioblastoma; Signaling
资金
- National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health (NIH) [T32 AR007108, K08 AR063696, R01 AR063709]
- National Cancer Institute of the NIH [R01 CA170653]
- Rheumatology Research Foundation
- Arthritis National Research Foundation
Cadherins are homophilic cell-to-cell adhesion molecules that help cells respond to environmental changes. Newly formed cadherin junctions are associated with increased cell phosphorylation, but the pathways driving this signaling response are largely unknown. Since cadherins have no intrinsic signaling activity, this phosphorylation must occur through interactions with other signaling molecules. We previously reported that cadherin-11 engagement activates joint synovial fibroblasts, promoting inflammatory and degradative pathways important in rheumatoid arthritis (RA) pathogenesis. Our objective in this study was to discover interacting partners that mediate cadherin-11 signaling. Protein array screening showed that cadherin-11 extracellular binding domains linked to an Fc domain (cad11Fc) induced platelet-derived growth factor (PDGFR)-alpha phosphorylation in synovial fibroblasts and glioblastoma cells. PDGFRs are growth factor receptor tyrosine kinases that promote cell proliferation, survival, and migration in mesodermally derived cells. Increased PDGFR activity is implicated in RA pathology and associates with poor prognosis in several cancers, including sarcoma and glioblastoma. PDGFR alpha activation by cadherin-11 signaling promoted fibroblast proliferation, a signaling pathway independent from cadherin-11-stimulated IL-6 or matrix metalloproteinase (MMP)-3 release. PDGFR alpha phosphorylation mediated most of the cad11Fc-induced phosphatidyl-3-kinase (PI3K)/Akt activation, but only part of the mitogen-activated protein kinase (MAPK) response. PDGFR alpha-dependent signaling did not require cell cadherin-11 expression. Rather, cad11Fc immunoprecipitated PDGFR alpha, indicating a direct interaction between cadherin-11 and PDGFR alpha extracellular domains. This study is the first to report an interaction between cadherin-11 and PDGFR alpha and adds to our growing understanding that cadherin-growth factor receptor interactions help balance the interplay between tissue growth and adhesion.
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