Bmx Tyrosine Kinase Has a Redundant Function Downstream of Angiopoietin and Vascular Endothelial Growth Factor Receptors in Arterial Endothelium

Abstract

The Bmx gene, a member of the Tec tyrosine kinase gene family, is known to be expressed in subsets of hematopoietic and endothelial cells. In this study, mice were generated in which the first coding exon of the Bmx gene was replaced with the lacZ reporter gene by a knock-in strategy. The homozygous mice lacking Bmx activity were fertile and had a normal life span without an obvious phenotype. Staining of their tissues using ␤-galactosidase substrate to assess the sites of Bmx expression revealed strong signals in the endothelial cells of large arteries and in the endocardium starting between days 10.5 and 12.5 of embryogenesis and continuing in adult mice, while the venular endothelium showed a weak signal only in the superior and inferior venae cavae. Of the five known endothelial receptor tyrosine kinases tested, activated Tie-2 induced tyrosyl phosphorylation of the Bmx protein and both Tie-2 and vascular endothelial growth factor receptor 1 (VEGFR-1) stimulated Bmx tyrosine kinase activity. Thus, the Bmx tyrosine kinase has a redundant role in arterial endothelial signal transduction downstream of the Tie-2 and VEGFR-1 growth factor receptors.

Coordinating Etk/Bmx activation and VEGF upregulation to promote cell survival and proliferation

“…Together with the data of Flk-1/ KDR/VEGFR-2 being present in TR-BBB cells and HUVEC (this report and Zeng et al, 2001), it is conceivable to conclude that Etk induces VEGF expression and that subsequently the secreted VEGF binds to Flk-1/KDR/VEGFR-2 to modulate endothelial cellular processes in an autocrine manner. Studies with Etk/Bmx knockout mice demonstrated that Etk/ Bmx-null mice are viable and without an obvious phenotype, at least in the context of DBA/2 background (Rajantie et al, 2001). Although this observation suggests that Etk-mediated signaling may be a redundant pathway, it does not rule out the possibility that enhanced Etk-dependent signaling exerts a positive modulatory effect on various cell behaviors, rendering adaptive responses to noxious environment.…”

Functional Interaction of Caveolin-1 with Bruton's Tyrosine Kinase and Bmx

“…In light of this, it is possible that the vascular abnormality observed in these mice might reflect an up-regulation of the kinase activity of Bmx, an endothelial and epithelial specific tyrosine kinase that has been shown to be involved in various signaling events of angiogenesis and vascular disease (62,63).…”

Etk/Bmx Transactivates Vascular Endothelial Growth Factor 2 and Recruits Phosphatidylinositol 3-Kinase to Mediate the Tumor Necrosis Factor-induced Angiogenic Pathway

“…To test this hypothesis, we isolated Etk-null EC from Etk-null mice (35) to determine the role of Etk in TNF signaling. Mouse lung EC (MLEC) from Etk-null mice were isolated as described previously (23).…”