Ninein Is Expressed in the Cytoplasm of Angiogenic Tip-Cells and Regulates Tubular Morphogenesis of Endothelial Cells

• Objective— Angiogenesis is an integral part of many physiologicalprocesses but may also aggravate pathological conditions suchas cancer. Development of effective angiogenesis inhibitorsrequires a thorough understanding of the molecular mechanismsregulating vessel formation. The aim of this project was toidentify proteins that regulate tubular morphogenesis of endothelialcells.Methods and Results— Phosphotyrosine-dependent affinity-purificationand mass spectrometry showed tyrosine phosphorylation of nineinduring tubular morphogenesis of endothelial cells. Ninein wasrecently identified as a centrosomal microtubule-anchoring protein.Our results show that ninein is localized in the cytoplasm inendothelial cells, and that it is highly expressed in the vasculaturein normal and pathological human tissues. Using embryoid bodiesas a model of vascular development, we found that ninein isabundantly expressed in the cytoplasm of endothelial cells duringsprouting angiogenesis, in particular in the sprouting tip-cell.In accordance, siRNA-dependent silencing of ninein in endothelialcells inhibited tubular morphogenesis.Conclusions— In this study, we show that ninein is expressedin developing vessels and in endothelial tip cells, and thatninein is critical for formation of the vascular tube. Thesedata strongly implicate ninein as an important new regulatorof angiogenesis.Proteins orchestrating morphological changes accompanying formationof the vascular tube constitute new targets for antiangiogenictherapy. In this study, we identify the microtubule-anchoringprotein ninein as an important new regulator of tubular morphogenesisof endothelial cells. This is the first report of a functionalrole of ninein in angiogenesis.

Nyckelord

ninein

angiogenesis

tubular morphogenesis

microtubule

endothelial

MEDICINE

MEDICIN

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