| First Author | Liao Z | Year | 2015 |
| Journal | Blood | Volume | 125 |
| Issue | 12 | Pages | 1995-2004 |
| PubMed ID | 25587038 | Mgi Jnum | J:221917 |
| Mgi Id | MGI:5641830 | Doi | 10.1182/blood-2014-09-603035 |
| Citation | Liao Z, et al. (2015) Interaction of kindlin-2 with integrin beta3 promotes outside-in signaling responses by the alphaVbeta3 vitronectin receptor. Blood 125(12):1995-2004 |
| abstractText | The bidirectional signaling and hemostatic functions of platelet alphaIIbbeta3 are regulated by kindlin-3 through interactions with the beta3 cytoplasmic tail. Little is known about kindlin regulation of the related "vitronectin receptor," alphaVbeta3. These relationships were investigated in endothelial cells, which express alphaVbeta3 and kindlin-2 endogenously. "beta3DeltaRGT" knock-in mice lack the 3 C-terminal beta3 tail residues, whereas in "beta3/beta1(EGK)" mice, RGT is replaced by the corresponding residues of beta1. The wild-type beta3 tail pulled down kindlin-2 and c-Src in vitro, whereas beta3DeltaRGT bound neither protein and beta3/beta1(EGK) bound kindlin-2, but not c-Src. beta3DeltaRGT endothelial cells, but not beta3/beta1(EGK) endothelial cells, exhibited migration and spreading defects on vitronectin and reduced sprouting in 3-dimensional fibrin. Short hairpin RNA silencing of kindlin-2, but not c-Src, blocked sprouting by beta3 wild-type endothelial cells. Moreover, defective sprouting by beta3DeltaRGT endothelial cells could be rescued by conditional, forced interaction of alphaVbeta3DeltaRGT with kindlin-2. Stimulation of beta3DeltaRGT endothelial cells led to normal extracellular ligand binding to alphaVbeta3, pin-pointing their defect to one of outside-in alphaVbeta3 signaling. beta3DeltaRGT mice, but not beta3/beta1(EGK) mice, exhibited defects in both developmental and tumor angiogenesis, responses that require endothelial cell function. Thus, the beta3/kindlin-2 interaction promotes outside-in alphaVbeta3 signaling selectively, with biological consequences in vivo. |
