The lysine-rich C-terminal tail of heparin affin regulatory peptide is required for mitogenic and tumor formation activities

Heparin affin regulatory peptide (HARP) is a 18-kDa heparin-binding polypep tide that is highly expressed in developing tissues and in several primary human tumors. It seems to play a key role in cellular growth and differenti ation. In vitro, HARP displays mitogenic, angiogenic, and neurite outgrowth activities. It is a secreted protein that is organized in two beta -sheet domains, each domain containing a cluster of basic residues. To assess dete rminants involved in the biological activities of HARP, C-terminally trunca ted proteins were produced in Chinese hamster ovary-K1 cells and tested for their mitogenic, tumor formation in nude mice and neurite outgrowth activi ties. Our data clearly indicate that the residues 111-136 of the lysine-ric h C-terminal domain are involved in the mitogenic and tumor formation activ ities of HARP. Correlatively, no signal transduction was detected using the corresponding mutant, suggesting the absence of HARP binding to its high a ffinity receptor. However, this C-terminal domain of HARP is not involved i n the neurite outgrowth activity. We also demonstrate that HARP signal pept ide cleavage could led to two maturated forms that are both but differentia lly mitogenic.