Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
10802914 | Biochimica et Biophysica Acta (BBA) - Molecular Cell Research | 2010 | 10 Pages |
Abstract
Integrin signaling is comprised of well-characterized pathways generally involved in cell survival. α9β1 integrin has recently become a target of study and has been shown to present pro-survival effects on neutrophils. However, there are no detailed studies on how α9β1 integrin-coupled signaling pathways interact and how they converge to finally modulate spontaneous apoptosis in neutrophils. In this regard we sought to investigate the main signaling events triggered by α9β1 integrin engagement and how these signaling pathways modulate the apoptotic program of human neutrophils. Using VLO5, a snake venom disintegrin shown to bind to α9β1 integrin in neutrophils, we demonstrate that α9β1 integrin engagement leads to the activation of integrin signaling pathways and potently reduces neutrophil spontaneous apoptosis. These effects are dependent on the activation of PI3K and MAPK pathways, since both LY294002 (PI3K inhibitor) or PD95059 (MEK inhibitor) reverted the effects of VLO5/α9β1 interaction. Moreover we show that VLO5/α9β1 engagement induces NF-κB nuclear translocation and increases the ratio between anti- and pro-apoptotic proteins by inducing the degradation of pro-apoptotic protein Bad and increasing the expression of anti-apoptotic protein Bcl-xL. VLO5 also inhibited the early steps of neutrophil spontaneous apoptosis by preventing Bax translocation to the outer mitochondrial membrane and consequent cytochrome c release. In conclusion, as the mechanistic details of α9β1 integrin signaling pathways in human neutrophils becomes clearer, it should become possible to develop new therapeutic agents for human diseases where neutrophils play a prominent role.
Keywords
ECMNF-κBPI3KJnkFAKERKVCAM-1Bcl-xLPMNc-Jun KinaseADAMIntegrina disintegrin and metalloproteaseApoptosisSignalingnuclear factor-κBDisintegrinphosphatidylinositol-3-kinasepolymorphonuclear leukocyteExtracellular matrixvascular cell adhesion molecule-1neutrophilextracellular signal-regulated kinasefocal adhesion kinase
Related Topics
Life Sciences
Biochemistry, Genetics and Molecular Biology
Biochemistry
Authors
Roberta F. Saldanha-Gama, João A. Moraes, Andrea Mariano-Oliveira, Ana Lucia Coelho, Erin M. Walsh, Cezary Marcinkiewicz, Christina Barja-Fidalgo,