CD151 mediates netrin‐1‐induced angiogenesis through the Src‐FAK‐Paxillin pathway

Abstract

Crosstalk between the nervous and vascular systems is important during development and in response to injury, and the laminin‐like axonal guidance protein netrin‐1 has been studied for its involvement in angiogenesis and vascular remodelling. In this study, we examined the role of netrin‐1 in angiogenesis and explored the underlying mechanisms. The effect of netrin‐1 on brain tissues and endothelial cells was examined by immunohistochemistry and western blotting in a middle cerebral artery occlusion model and in human umbilical vein endothelial cells. Cell proliferation and cell cycle progression were assessed by the MTT assay and flow cytometry, and the Transwell and tube formation assays were used to examine endothelial cell motility and function. Netrin‐1 up‐regulated CD151 and VEGF concomitant with the activation of focal adhesion kinase (FAK), Src and Paxillin in vitro and in vivo and the induction of cell proliferation, migration and tube formation in vitro. Silencing of CD151 abolished the effects of netrin‐1 on promoting cell migration and tube formation mediated by the activation of FAK/Src signalling. Netrin‐1 promoted angiogenesis in vitro and in vivo by activating the FAK/Src/Paxillin signalling pathway through a mechanism dependent on the expression of the CD151 tetraspanin, suggesting the existence of a netrin‐1/FAK/Src/CD151 signalling axis involved in the modulation of angiogenesis.

Netrin‑1 induces the proliferation of gastric cancer cells via the ERK/MAPK signaling pathway and FAK activation

“…Previous studies have reported that FAK may be one of the primary downstream effectors of NTN1, functioning through the receptors DCC and neogenin (15,16). Furthermore, it has been reported that NTN1-induced cell proliferation and migration is mediated by the activation of FAK (17,25). The results of the present study suggest that FAK phosphorylation was decreased following NTN1 knockdown in GC cells, whereas NTN1 overexpression had the opposite effect.…”

Netrin-1 attenuates brain injury after middle cerebral artery occlusion via downregulation of astrocyte activation in mice

“…NT-1 also inhibited the notch signaling pathway after ischemic stroke [ 34 ]. In the process of angiogenesis and vascular remodeling, an NT-1/focal adhesion kinase (FAK)/Src signaling axis was also reported to be an important pathway [ 35 ]. In addition, NT-1 phosphorylated AMP-activated protein kinase (AMPK) and reduced the phosphorylation of mammalian target of rapamycin (mTOR) and P70S6K in a spinal cord injury model [ 36 ].…”

“…Molecular effectors are crucial in regulating the effect of NT-1. When introduced to proliferating endothelial cells, NT-1 was reported to increase the expression of inducible nitric oxide synthase (iNOS) and cluster of differentiation (CD) 151 [ 31 , 35 ]. NT-1 was also shown to be a regulator of nuclear factor kappa B (NF-κB) when inhibiting prostaglandin E2 (PGE-2) production [ 39 ].…”

Convergence of eicosanoid and integrin biology: Role of Src in 12-LOX activation

“…Other proteins such as syndecan-1 as well as tetraspanin CD151 that are known to regulate, relate to, or interact with ITGB4, are also implicated in diverse processes such as the examples used here of viral infection and cancer [69], and also signal through Src [70]. This cohort of proteins has likewise been isolated together with the integrin in secreted microvesicles and exosomes [71–73], where 12-HETE can also be found [54], thereby implicating this axis in tissue programming.…”