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

Abstract

The angiopoietins have recently joined the members of the vascular endothelial growth factor family as the only known growth factors largely specific for vascular endothelium. The angiopoietins include a naturally occurring agonist, angiopoietin-1, as well as a naturally occurring antagonist, angiopoietin-2, both of which act by means of the Tie2 receptor. We now report our attempts to use homologybased cloning approaches to identify new members of the angiopoietin family. These efforts have led to the identification of two new angiopoietins, angiopoietin-3 in mouse and angiopoietin-4 in human; 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 receptors. Although angiopoietin-3 and angiopoietin-4 are strikingly more structurally diverged from each other than are the mouse and human versions of angiopoietin-1 and angiopoietin-2, they appear to represent the mouse and human counterparts of the same gene locus, as revealed in our chromosomal localization studies of all of the angiopoietins in mouse and human. The structural 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 angiopoietin-3 appears to act as an antagonist, whereas angiopoietin-4 appears to function as an agonist.

Cotargeting of VEGFR-1 and -3 and angiopoietin receptor Tie2 reduces the growth of solid human ovarian cancer in mice

“…15 Angiopoietins (Ang1-4) are ligands for the tyrosine kinase receptor Tie2. [16][17][18] Ang1 activates Tie2 signaling pathways and promotes the recruitment of pericytes and smooth muscle cells to the developing vessels 16,19 and contributes to tumor dissemination and metastasis. 20 Ang2, on the contrary, functions in a context-dependent manner as an antagonist promoting either blood vessel growth or regression depending on the levels of other growth factors, such as VEGF-A.…”

“…22 Ang2 is also required for normal lymphatic vessel formation. 23 Mouse Ang3 and human Ang4 are interspecies orthologues, 18 whose functions have not yet been clarified. The function of Tie1 is less well characterized than that of Tie2 because of the lack of its own specific ligands, although it has been recently shown that the Tie1 receptor can interact with Tie2 and signal as a heterodimeric complex.…”

Mechanisms of angiogenesis and their use in the inhibition of tumor growth and metastasis

“…To date there are four known angiopoietins, which all bind to the Tie-2 receptor, mediating vessel stabilization signals, whereas the Tie-1 receptor has so far no known ligand (Figure 2) Maisonpierre et al, 1997;Kim et al, 1999;Valenzuela et al, 1999). The phenotypes of Tie-2 and Ang-1 de®cient mice suggest a role for this ligand ± receptor system in maintaining communication between endothelial cells and the surrounding mesenchyme, in order to establish stable cellular and biochemical interactions between endothelial cells and pericytes/ smooth muscle cells (Dumont et al, 1994;Puri et al, 1995;Suri et al, 1997).…”

The enigmatic role of angiopoietin-1 in tumor angiogenesis

“…The Angiopoietin family of growth factors is comprised of four family members that bind to the Tie2 tyrosine kinase receptor with different outcomes. Angiopoietin-1 (Ang1), the main ligand for Tie2 [18,19], and -4 [20] are agonistic ligands, whereas Angiopoietin-2 (Ang2) and -3 can serve as antagonistic ligands [20,21]. Although Ang1 does not stimulate proliferation of endothelial cells [18], in vitro Ang1 can induce endothelial migration [22], tubule formation [23] and sprouting [24,25], and survival from a variety of apoptotic insults [26][27][28][29], suggesting that Ang1 can be a potent pro-angiogenic factor.…”