c‐Abl tyrosine kinase regulates neutrophil crawling behavior under fluid shear stress via Rac/PAK/LIMK/cofilin signaling axis

Abstract

The excessive recruitment and improper activation of polymorphonuclear neutrophils (PMNs) often induces serious injury of host tissues, leading to inflammatory disorders. Therefore, to understand the molecular mechanism on neutrophil recruitment possesses essential pathological and physiological importance. In this study, we found that physiological shear stress induces c-Abl kinase activation in neutrophils, and c-Abl kinase inhibitor impaired neutrophil crawling behavior on ICAM-1. We further identified Vav1 was a downstream effector phosphorylated at Y174 and Y267. Once activated, c-Abl kinase regulated the activity of Vav1, which further affected Rac1/PAK1/LIMK1/cofilin signaling pathway. Here, we demonstrate a novel signaling function and critical role of c-Abl kinase during neutrophil crawling under physiological shear by regulating Vav1. These findings provide a promising treatment strategy for inflammation-related disease by inactivation of c-Abl kinase to restrict neutrophil recruitment.

c-Abl regulates YAPY357 phosphorylation to activate endothelial atherogenic responses to disturbed flow

“…Several kinases from different families, including focal adhesion kinase (FAK) and c-Src, mediate the signal transduction of integrins (22). c-Abl has been shown to be colocalized with integrin α5 and activated in cells subjected to fibronectin treatment (23) or fluid shear stress (24). Furthermore, with the emerging importance of NRTKs in neurodegenerative diseases, chronic myeloid leukemia, and carcinogenesis, tyrosine kinase inhibitors are being used in the clinic (21).…”

Melatonin enhances thrombopoiesis through ERK1/2 and Akt activation orchestrated by dual adaptor for phosphotyrosine and 3‐phosphoinositides

“…Because Rac1/Cdc42 phosphorylation is a negative indicator of Rac1/Cdc42 GTPase activation, MT likely causes activation of Rac1/Cdc42 GTPase in MKs (Figure D,E). This activation is supported by a decrease in PAK, LIMK, and cofilin phosphorylation (Figure F‐J), as cofilin phosphorylation is mediated by Rac1/Cdc42 effector PAK, via the activation of the downstream effector LIMK . Interestingly, we found that the Rac1/Cdc42 GTPase inhibitors, especially the Rac inhibitor EHop‐016, significantly blocked the activation induced by MT, which was revealed by a more prominent Rac1/Cdc42 phosphorylation after pretreatment with EHop‐016 compared with that after pretreatment with the Cdc42 inhibitor ZCL278.…”

“…This activation is supported by a decrease in PAK, LIMK, and cofilin phosphorylation ( Figure 4F-J), as cofilin phosphorylation is mediated by Rac1/Cdc42 effector PAK, via the activation of the downstream effector LIMK. 19,20 Interestingly, we found that the Rac1/Cdc42 GTPase inhibitors, especially the Rac inhibitor EHop-016, significantly blocked the activation induced by MT, which was revealed by a more prominent Rac1/Cdc42 phosphorylation after pretreatment with EHop-016 compared with that after pretreatment with the Cdc42 inhibitor ZCL278. Therefore, the activation of Rac1/Cdc42 GTPase is mainly mediated by Rac GTPase (Figure 4J,K).…”

Inhibition of LIM kinase reduces contraction and proliferation in bladder smooth muscle

“…However, whether this symptom improvement was completely attributed to SR7826/LIMKi3-induced detrusor relaxation may not be concluded from our data. OAB symptoms may also be associated with inflammation in the bladder, while LIMK has been indicated as a regulator during inflammatory processes in some other diseases 54 , 55 . However, any additional effect of LIMK on the inflammation associated OAB remains unclear, and needs further exploration.…”