A novel TNF receptor family member binds TWEAK and is implicated in angiogenesis

TWEAK is a member of the TNF ligand family that induces angiogenesis in viv o. We report cloning of a receptor for TWEAK (TweakR) from a human umbilica l vein endothelial cell (HUVEC) library. The mature form of TweakR has only one hundred and two amino acids and six cysteine residues in its extracell ular region. Five different assays demonstrate TWEAK-TweakR binding, and th e interaction affinity constant (Kd) is within a physiologically relevant r ange of 2.3 +/- 0.1 nM. The TweakR cytoplasmic domain binds TRAFs 1, 2, and 3. Cross-linking of TweakR induces HUVEC growth, and mRNA levels are upreg ulated in vitro by a variety of agents and in vivo following arterial injur y. Soluble TweakR inhibits endothelial cell migration in vitro and corneal angiogenesis in vivo.