期刊
JOURNAL OF EXPERIMENTAL MEDICINE
卷 212, 期 7, 页码 1021-1041出版社
ROCKEFELLER UNIV PRESS
DOI: 10.1084/jem.20150354
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资金
- National Institutes of Health (NIH) [NHLBI F30 HL116100-01A1, NIH R37 HL064774, R01 HL046849, R01 GM62328, R01 GM107442]
- Sidney & Bess Eisenberg Memorial Fund
- Grants-in-Aid for Scientific Research [24115005, 26117714] Funding Source: KAKEN
CD99 is a critical regulator of leukocyte transendothelial migration (TEM). How CD99 signals during this process remains unknown. We show that during TEM, endothelial cell (EC) CD99 activates protein kinase A (PKA) via a signaling complex formed with the lysine-rich juxtamembrane cytoplasmic tail of CD99, the A-kinase anchoring protein ezrin, and soluble adenylyl cyclase (sAC). PKA then stimulates membrane trafficking from the lateral border recycling compartment to sites of TEM, facilitating the passage of leukocytes across the endothelium. Pharmacologic or genetic inhibition of EC sAC or PKA, like CD99 blockade, arrests neutrophils and monocytes partway through EC junctions, in vitro and in vivo, without affecting leukocyte adhesion or the expression of relevant cellular adhesion molecules. This is the first description of the CD99 signaling pathway in TEM as well as the first demonstration of a role for sAC in leukocyte TEM.
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