期刊
出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.2002162118
关键词
chemotaxis; adaptation; small GTPase Ras; GAP; CAPRI
资金
- NIH Intramural Fund from the National Institute of Allergy and Infectious Diseases, NIH
The study demonstrates the important role of CAPRI in mediating GPCR activation-induced Ras adaptation in human neutrophils. By reducing cell sensitivity, CAPRI enables neutrophils to chemotax through higher concentration gradients of chemoattractants.
Neutrophils sense and migrate through an enormous range of che-moattractant gradients through adaptation. Here, we reveal that in human neutrophils, calcium-promoted Ras inactivator (CAPRI) locally controls the GPCR-stimulated Ras adaptation. Human neu-trophils lacking CAPRI (capri(kd)) exhibit chemoattractant-induced, nonadaptive Ras activation; significantly increased phosphoryla-tion of AKT, GSK-3 alpha/3 beta, and cofilin; and excessive actin polymeri-zation. capri(kd) cells display defective chemotaxis in response to high-concentration gradients but exhibit improved chemotaxis in low-or subsensitive-concentration gradients of various chemoat-tractants, as a result of their enhanced sensitivity. Taken together, our data reveal that CAPRI controls GPCR activation-mediated Ras adaptation and lowers the sensitivity of human neutrophils so that they are able to chemotax through a higher-concentration range of chemoattractant gradients.
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