Angiopoietins 3 and 4: Diverging gene counterparts in mice and humans

The angiopoietins have recently joined the members of the vascular endothel ial growth factor family as the only known growth factors largely specific for vascular endothelium. The angiopoietins include a naturally occurring a gonist, angiopoietin-1, as well as a naturally occurring antagonist, angiop oietin-2, both of which act by means of the Tie2 receptor. We now report ou r attempts to use homology-based cloning approaches to identify new members of the angiopoietin family. These efforts have led to the identification o f two new angiopoietins, angiopoietin-3 in mouse and angiopoietin-3 in huma n; we have also identified several more distantly related sequences that do not seem to be true angiopoietins, in that they do not bind to the Tie rec eptors. Although angiopoietin-3 and angiopoietin-4 are strikingly more stru cturally diverged from each other than are the mouse and human versions of angiopoietin-1 and angiopoietin-2, they appear to represent the mouse and h uman counterparts of the same gene locus, as revealed in our chromosomal lo calization studies of all of the angiopoietins in mouse and human. The stru ctural divergence of angiopoietin-3 and angiopoietin-4 appears to underlie diverging functions of these counterparts. Angiopoietin-3 and angiopoietin- 4 have very different distributions in their respective species, and angiop oietin-3 appears to act as an antagonist, whereas angiopoietin-4 appears to function as an agonist.