Ras Inhibitor CAPRI Enables Neutrophils to Chemotax Through a Higher-Concentration Range of Gradients

Neutrophils sense and migrate through an enormous range of chemoattractant gradients through adaptation. Here, we reveal that, in human neutrophils, Calcium-promoted Ras inactivator (CAPRI) locally controls the GPCR-stimulated Ras adaptation. Human neutrophils lacking CAPRI (caprikd) exhibit chemoattractant-induced non-adaptive Ras activation; significantly increased phosphorylation of AKT, GSK3a/3b,and cofilin; and excessive actin polymerization. caprikd cells display defective chemotaxis in response to high-concentration gradients but exhibit improved chemotaxis in low- or subsensitive-concentration gradients of various chemoattractants 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.