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J. Biol. Chem., Vol. 280, Issue 12, 10945-10954, March 25, 2005

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Hepatoma-derived Growth Factor

SIGNIFICANCE OF AMINO ACID RESIDUES 81–100 IN CELL SURFACE INTERACTION AND PROLIFERATIVE ACTIVITY^*

Mekky M. Abouzied, Heba Mahmoud El-tahir, Lars Prenner, Hanns Häberlein, Volkmar Gieselmann, and Sebastian Franken

From the Institut für Physiologische Chemie, Rheinische Friedrich-Wilhelms Universität, Nussallee 11, 53115 Bonn, Germany

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.

Received for publication, December 29, 2004

^* This work was supported by a Channel system scholarship of the Egyptian government/El-Minia University (to M. M. A.) and BONFOR Grant O-161.0020 (to S. F.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed. Tel.: 49-228-73-4744; Fax: 49-228-73-2416; E-mail: franken{at}institut.physiochem.uni-bonn.de.

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