Nerve growth factor-beta (NGF β) and a NGF β-immunoreactive protein derived from human prostatic stromal cell secretory protein (hPS) have been shown to stimulate the growth of prostate epithelial cells. An NGF β-immunoreactive protein has been localized to the stroma of human prostate tissues, and a low affinity NGF receptor (gp75NGFR) has been localized to the adjacent epithelia, consistent with the paracrine regulation of prostate growth. Interestingly, gp75NGFR is progressively lost during neoplastic progression of the human prostate. In this report we have characterized the expression of the signal-transducing component of the NGF receptor, the Trk tyrosine receptor kinase, in prostate epithelial cells that bind exogenous NGF β and an endogenous NGF β-immunoreactive protein in hPS. In this context, a pan-Trk antibody that recognizes all of the members of the Trk receptor family (TrkA, TrkB, and TrkC) specifically localized expression of the Trk receptor to the epithelial component of normal prostate tissue, benign prostatic hyperplasia, and adenocarcinoma tissue. The binding of [125I]NGF β to the surface of primary cultures of human prostate epithelia and the TSU-pr1 human metastatic prostate tumor cell line was displaced with either excess cold NGF β or hPS, whereas binding was not displaced by epidermal growth factor or platelet-derived growth factor. Scatchard plot analysis of [125I]NGF β binding to these cells identified a low affinity binding site (Kd = 1.9 × 10(−9) M) and a high affinity binding site (Kd = 1.8 × 10(−11) M) on the primary prostate epithelia, whereas only a high affinity binding site (Kd = 1.3 × 10(−11) M) was observed on the TSU-pr1 tumor cells. Stimulation of TSU-pr1 cells with either NGF β or hPS induced tyrosine phosphorylation of Trk proteins, whereas no phosphorylation was evident in untreated cells, cells treated with hPS immunoprecipitated with anti-NGF β antibody, or brain-derived neurotrophic factor- and neurotrophin-3-treated cells. The Trk protein was also observed in these cells by immunoblot analysis with pan-Trk antibody. These results demonstrate a functional Trk receptor in the epithelia of the human prostate that is responsive to exogenous NGF β and an endogenous NGF β-immunoreactive protein in hPS, thereby supporting the concept of the paracrine regulation of growth in the human prostate via a stromal neurotrophin-epithelial Trk receptor interaction.
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