Regulatory Mechanism Of C-Abl Kinase In β2Integrin-mediated Neutrophil Migration

PMN is an essential component of the innate immune system. When acute inflammationoccurs, neutrophils are rapidly recruited and extravasated from blood into infection sites,where they destroy the invading microorganisms by phagocytosis of pathogens and releasingseveral antimicrobial chemicals. However, the excessive and improper recruitment ofneutrophils usually result in serious tissue injury. Therefore, understanding the molecularmechanism underlying the recruitment and migration of neutrophil is of great physiologicaland pathological importance.Cell migration is a highly complicated and regulated process, in which the regulation ofactin cytoskeleton plays a pivotal role by promoting the formation of membrane protrusions atthe leading edge and providing a driving force, together with molecular motors, to move thecell body. Molecules involved in regulating actin cytoskeleton rearrangement have been wellidentified. A variety of adhesion molecules is required for neutrophil migration, in which theβ2integrin plays an important role in the stable adhesion between neutrophils and activatedvascular endothelial and transendothelial migration. β2integrin family is highly expressedadhesion molecules in the neutrophil cell surface, they are formed by a common β subunitwith four α subunit, forming non-covalent heterodimer. In resting neutrophils, β2integrin ispresent in low-affinity state. Once the stimulation of chemokines, β2integrin is rapidactivated, and adjust the dynamic changes of the cytoskeleton by the"outside-in" signalingpathway, and ultimately regulate cell migration movement. However, the molecularmechanism for the β2integrin-mediated neutrophil migration is still unclear. The engagementof β2integrin can activate a variety of non-receptor tyrosine kinase, induce cell cytoskeletonrearrangement. c-Abl kinase, a nonreceptor tyrosine kinase expressed ubiquitously inmammalian cells, serves as an important link in signal transduction pathways that promoteactin dynamics and cytoskeletal rearrangement. Especially, c-Abl kinase is a key factorinvolved in the formation of membrane ruffling and cell spreading, as well as the dynamicformation or extension of filopodia and lamellipodia in response to extracellular signal or adhesion stimulation. However, the mechanisms underlying the regulation of actincytoskeleton by c-AbI kinase and the downstream effector of c-AbI kinase, as well as theirroles in neutrophil migration, have not been well identified.The rearrangement of actin cytoskeleton is highly influenced by the activity of Rho familyGTPases. One extensively studied family of GEF, which is responsible for the enzymaticactivity of Rho GTPases, is the Dbl family proto-oncogene Vav. Vav1, the first discoveredmember, is a hematopoietic, cell-specific signal protein, and it is involved in the alterations ofcell shape and motility by triggering cytoskeletal changes, as demonstrated by its ability toinduce membrane ruffles and lamellipodia formation.In the present study, a signaling mechanism that controls actin polymerization andmembrane protrusion dynamics at the leading edge during β2integrin-dependent neutrophilmigration is well-defined, with c-AbI kinase playing a central, regulatory role. In addition, wefind Vav1colocalizes and interacts with c-AbI kinase at the leading edges of migratingneutrophils. Vav1is phosphorylated directly by c-AbI kinase at Tyr-267in the DH domain.Taken together, we demonstrate a critical role of c-AbI kinase in neutrophil migration byregulating Vav1activity, providing the feasibility to target c-AbI kinase for the amelioration ofacute inflammation-related diseases.