期刊
SCIENCE SIGNALING
卷 3, 期 149, 页码 -出版社
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/scisignal.2001158
关键词
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资金
- National Institute of Allergy and Infectious Diseases [RO1 AI 042819]
- NIH [U01AI077821, R0-1 DK 55003, R0-1 DK56930, R21CA137292, P30 DK41301]
- National Heart, Lung and Blood Institute [RO1 HL 090995]
Among transplant recipients, those who produce antibodies against the donor's human leukocyte antigens (HLAs) are at higher risk for antibody-mediated rejection and transplant vasculopathy, which is a progressive, vasculo-occlusive disease that results in ischemic injury and deterioration of organ function. Antibodies against HLA class I (HLA-I) molecules are thought to contribute to transplant vasculopathy by triggering signals that elicit the activation and proliferation of endothelial cells. Here, we demonstrate a molecular association between HLA-I and the integrin beta(4) subunit after the stimulation of endothelial cells with HLA-I-specific antibodies. Knockdown of integrin beta(4) in these cells abrogated the ability of HLA-I to stimulate the phosphorylation of the kinases Akt, extracellular signal-regulated kinase (ERK), and Src, as well as cellular proliferation. Similarly, reducing the abundance of HLA-I suppressed integrin beta(4)-mediated phosphorylation of ERK and the migration of endothelial cells on laminin-5, a component of the extracellular matrix. These results indicate a mutual dependency between HLA-I and the integrin beta(4) subunit to stimulate the proliferation and migration of endothelial cells, which may be important in promoting transplant vasculopathy and tumor angiogenesis.
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