HDGF belongs to a family of proteins containing a well-conserved N-terminal amino acid sequence,
67,68 which includes the HDGF-related proteins (HDGFRP-1 to -4) and lens epithelial factor.
69 Although HDGF, HDGFRP-2, and HDGFRP-3 are expressed in developing neurons, their biological functions in the adult central nervous system are not well defined.
69 It has been reported that HDGF is localized to the nuclei of neurons, astrocytes, and oligodendrocytes in adulthood.
70 HDGFRP-3 has also been found to promote neurite outgrowth in mouse cortical neurons through a direct interaction with tubulin.
69 Outside the nervous system, HDGF knockdown induces Bad- and Fas-mediated apoptosis in human cancer cells,
28 and has growth-stimulating activity in fibroblasts, hepatoma cells, vascular smooth muscle cells, and endothelial cells.
67,71–73 It has been shown that the mitogenic activity of HDGF is dependent on nuclear localization or translocation.
74,75 Other identified roles for HDGF include nephrogenesis, vascular development, and tumorigenesis.
72,74,76 HDGF, like other trophic factors, has been postulated to act via receptor binding at the cell surface; however, the HDGF receptor(s) has yet to be identified. Despite this, it was recently demonstrated that residues 81 to 100 are critical for binding to the cell surface and stimulating proliferation in 3T3 fibroblasts.
77 Furthermore, heparin sulfate on the cell surface appears to be necessary for HDGF to exert biological effects that are partially dependent on activation of the MAPK pathway.
78 Our iTRAQ proteomics show that HDGF is expressed in the adult rat retina, in addition to previous data showing that HDGF is expressed in porcine fetal retinal pigment epithelium.
79 Furthermore, the present findings also show that HDGF has biological effects in the adult retina, as a potent neuroprotective factor.