期刊
JOURNAL OF CELL SCIENCE
卷 128, 期 5, 页码 992-1000出版社
COMPANY BIOLOGISTS LTD
DOI: 10.1242/jcs.161497
关键词
Chemotaxis; RHOA; Polarization; FAM65B; Neutrophil
类别
资金
- National Institutes of Health (NIH) [HL108430, HL120465]
- AHA Early Investigator Award
- National Natural Science Foundation of China [31400753, 31071193, 81171964]
- China Postdoctoral Science Foundation [2013M541461]
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [R01HL108430, R01HL120465] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES [R21AI094525] Funding Source: NIH RePORTER
A hallmark of neutrophil polarization is the back localization of active RHOA and phosphorylated myosin light chain (pMLC, also known as MYL2). However, the mechanism for the polarization is not entirely clear. Here, we show that FAM65B, a newly identified RHOA inhibitor, is important for the polarization. When FAM65B is phosphorylated, it binds to 14-3-3 family proteins and becomes more stable. In neutrophils, chemoattractants stimulate FAM65B phosphorylation largely depending on the signals from the front of the cells that include those mediated by phospholipase C beta (PLC beta) and phosphoinositide 3-kinase gamma (PI3K gamma), leading to FAM65B accumulation at the leading edge. Concordantly, FAM65B deficiency in neutrophils resulted in an increase in RHOA activity and localization of pMLC to the front of cells, as well as defects in chemotaxis directionality and adhesion to endothelial cells under flow. These data together elucidate a mechanism for RHOA and pMLC polarization in stimulated neutrophils through direct inhibition of RHOA by FAM65B at the leading edge.
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