Hepatoma-derived Growth Factor

Abstract

Hepatoma-derived growth factor (HDGF) has proliferative, angiogenic, and neurotrophic activity. It plays a putative role in the development and progression of cancer. When expressed in cells, the mitogenic activity of HDGF depends on its nuclear localization, but it also stimulates proliferation when added to the cell culture medium. A cell surface receptor for HDGF has not been identified so far. We investigated the interaction of various purified recombinant HDGF fusion proteins with the cell surface of NIH 3T3 fibroblasts. We showed that binding of a HDGF-␤-galactosidase fusion protein to the cell surface of NIH 3T3 fibroblasts was saturable, occurred with high affinity (K D ‫؍‬ 14 nM), and had a proliferative effect. We identified a peptide comprising amino acid residues 81-100 within the amino-terminal part of HDGF that bound to the cell surface of NIH 3T3 cells with saturation and affinity values similar to those of HDGF. When added to primary human fibroblasts, this peptide stimulated proliferation. Substitution of a single amino acid (K96A) within this peptide was sufficient to abolish its binding to the cell surface and its proliferative activity. In contrast, when expressed transiently in NIH 3T3 cells, a HDGF-␤-galactosidase fusion protein in which amino acid residues 81-100 were deleted still had proliferative activity, whereas a fusion protein containing only the 81-100 peptide did not. Our results suggest the existence of a plasma membrane-located HDGF receptor for which signaling depends on amino acid residues 81-100 of HDGF. This region differs from the one that has been recently identified to be essential for mitogenic activity depending on the nuclear localization of HDGF. Thus, HDGF exerts its proliferative activity via two different pathways.

Hepatoma-Derived Growth Factor Is a Novel Prognostic Factor for Patients with Pancreatic Cancer

“…Previous studies have shown the prognostic significance of cytoplasmic HDGF accumulation in hepatic and gastric cancers (20 -22), although the precise role of cytoplasmic localization of HDGF is still unclear. Recently, the existence of a plasma membrane-located HDGF receptor has been reported (29). Further investigation is necessary to clarify the biological effect of cytoplasmic HDGF localization.…”

Hepatoma-derived Growth Factor Predicts Disease Severity and Survival in Pulmonary Arterial Hypertension

“…Although HDGF was discovered in cell culture conditional media, implying a secretory mechanism, this secretory pathway and the potential presence of an HDGF receptor remain unknown. However, mitogen-activated protein kinase and p38 pathways were shown to be activated by exogenous HDGF stimulation, indicating the presence of receptormediated signal transduction pathways for HDGF (40,41). HDGF is reexpressed in smooth muscle cells in vivo during neointimal formation after injury, suggesting that HDGF plays additional roles in vascular remodeling (42).…”

Hepatoma‐derived growth factor‐related protein‐3: A new neurotrophic and neurite outgrowth‐promoting factor for cortical neurons

“…HDGF itself can act from the cell surface, possibly binding to an unknown receptor, or alternatively as an intracellular protein of primarily nuclear localization. Both kinds of action were shown to be independent of each other (Abouzied et al, 2005).…”

“…We demonstrate that, depending on its mode of application, HRP-3 has either neuroprotective or neurite outgrowth-promoting activity. In vivo, this might be realized by an interaction with extracellular matrix components such as heparan sulfate proteoglycans, which can bind members of the HDGF protein family (Dietz et al, 2002;Sue et al, 2004Sue et al, , 2007Abouzied et al, 2005).…”