J. Cell Biol.
© The Rockefeller University Press
0021-9525/97/01/389/10 $2.00
Volume 136, Number 2, January 27, 1997 389-398

Two Peptides Derived from the Nerve Growth Factor Precursor Are Biologically Active

Eleni Dicou,^* Beth Pflug, Marilyn Magazin,^§ Thérèse Lehy, Daniel Djakiew, Pascual Ferrara,^§ Véronique Nerrière,^* and Douglas Harvie^*

^* Institut National de la Santé et de la Recherche Médicale U298, Centre Hospitalier Universitaire, Angers 49033, France;  Department of Cell Biology, Georgetown University Medical Center, Washington DC, 20007; ^§ Sanofi Recherche, 31676 Labège, France; and  Institut National de la Santé et de la Recherche Médicale U10, Hôpital Bichat, 75877 Paris, Cedex 18, France

This report provides evidence that the proregion of the NGF precursor protein contains two novel bioactive peptides. The presence of pairs of basic amino acid (aa) residues in the NGF proregion suggests that two or three peptides other than NGF may be generated by proteolytic cleavage. Synthetic peptides of 29 aa (LIP1) and 38aa (LIP2) corresponding to the sequences 71 to 43 and 40 to 3 of the proNGF, respectively, were used in this study. ELISA specific for these two peptides revealed their presence in the rat intestine. LIP1 was localized by immunohistochemistry in endocrine cells of the intestinal epithelium, and LIP2 was immunoprecipitated from an intestinal extract. We also provide evidence for the presence of specific receptors for LIP2 in several cell lines. Scatchard analysis indicated the presence of a low affinity binding site with a K_d of ~10⁷ M and a high affinity binding site of 10⁹ M. Cross-linking studies revealed receptor forms of about 140 kD and 93 kD in a prostatic adenocarcinoma cell line.

LIP1 and LIP2 induced rapid F-actin redistribution in PC12 cells within 2 min of incubation, which suggests a role of LIP1 and LIP2 in the process of neurite outgrowth. Furthermore, both propeptides induced rapid tyrosine phosphorylation of the Trk protein in both prostatic adenocarcinoma cells and PC12 cells, thus implicating trk in their mechanism of action. These results support our hypothesis that two peptides within the NGF precursor protein are biologically active.

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