DIFFERENTIAL-EFFECTS OF HEPATOCYTE GROWTH-FACTOR ISOFORMS ON EPITHELIAL AND ENDOTHELIAL TUBULOGENESIS

Hepatocyte growth factor (HGF)/scatter factor (SF) is a pleiotropic cy tokine that acts as a mitogen, motogen, and morphogen for a variety of cell types. HGF/NK1 and HGF/NK2 are two naturally occurring truncated variants of HGF/SF, which extend from the NH, terminus through the fi rst and second kringle domain, respectively. Although these variants h ave been reported to have agonistic or antagonistic activity relative to HGF/SF in assays of cell proliferation and motility, their potentia l morphogenic activity has not been investigated, To address this issu e, we assessed the ability of HGF/NK1 and HGF/NK2 to induce tube forma tion by (a) MCF-10A mammary epithelial cells grown within collagen gel s and (b) human umbilical vein endothelial (HUVE) cells grown on Matri gel, We found that HGF/NK1 stimulated tubulogenesis by both MCF-10A an d HUVE cells, whereas HGF/NK2 did not stimulate tubulogenesis, but eff iciently antagonized the morphogenic effect of full-length HGF/SF. HGF /NK1 and HGF/NK2 also had agonistic and antagonistic effects, respecti vely, on MCF-10A cell proliferation and HUVE cell migration. These res ults demonstrate that HGF/NK1, which only consists of the NH2-terminal hairpin and first kringle domain, is sufficient to activate the intra cellular signaling pathways required to induce morphogenic responses i n epithelial and endothelial cells, In contrast, HGF/NK2, which differ s from HGF/NK1 by the presence of the second kringle domain, is devoid of intrinsic activity but opposes the effects of HGF/SF, The differen tial properties of the two HGF/SF isoforms provide a basis for the des ign of more potent HGF/SF agonists and antagonists.