The Role of Neuropeptide Processing Enzymes in Endocrine (Prostate) Cancer: EC 3.4.24.15 (EP24.15)

Swanson, Todd A.; Kim, Sandra I.; Myers, Michael; Pabon, Amanda; Philibert, Keith D.; Wang, Mina; Glucksman, Marc J.

doi:10.2174/0929866043406607

Cited by 16 publications

(24 citation statements)

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“…Studies using peptide agonists, at least in the case of opioid receptors, have shown that the co-endocytosed agonist is recycled back to the surface or processed in an acidic compartment, depending on the length of agonist treatment (17,53). Relatively few studies have focused on the enzymes that are responsible for post-endocytic peptide agonist degradation, although a number of peptidases have been shown to be capable of hydrolyzing neuroendocrine peptides including opioid peptides (2,45,54,55). Among them, an enzyme named enkephalinase (EC 3.4.24.11), originally thought to be solely responsible for enkephalin degradation, was soon shown to be able to degrade a number of other neuropeptides, and because it exhibited activity at neutral pH it was renamed "neutral endopeptidase" or neprilysin (6,8,56).…”

Section: Discussionmentioning

confidence: 99%

Opioid Receptor Function Is Regulated by Post-endocytic Peptide Processing

Gupta

Gomes

Wardman

et al. 2014

Journal of Biological Chemistry

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Background: Endothelin-converting enzyme-2 (ECE2) localizes to early endosomes and processes neuropeptides at nonclassical sites at acidic pH. Results: Inhibiting ECE2 activity impairs recycling and resensitization of ␦ opioid receptors. Conclusion: ECE2 regulates ␦ opioid receptor function by endocytic processing of opioid peptide substrates. Significance: Understanding the involvement of ECE2 in opioid receptor function could open novel avenues for developing pharmacotherapeutics to treat pain.

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Section: Discussionmentioning

confidence: 99%

Opioid Receptor Function Is Regulated by Post-endocytic Peptide Processing

Gupta

Gomes

Wardman

et al. 2014

Journal of Biological Chemistry

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“…Substrate specificity is dependent upon peptide size (< 17 amino acids), without preference for the amino acid sequence [21]. However, a hydrophobic amino acid residue in the P1 and P2 positions along with a bulky hydrophobic residue in the P3′ position increases specificity [22]. The results of studies show that GnRH-(1–5) is biologically active and supports EP24.15’s role as an extracellular processing peptidase and converting enzyme.…”

Section: Control Of the Lh Surgementioning

confidence: 99%

Hormonal Regulation of Female Reproduction

et al. 2012

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Reproduction is an event that requires the coordination of peripheral organs with the nervous system to ensure that the internal and external environments are optimal for successful procreation of the species. This is accomplished by the hypothalamic-pituitary-gonadal axis that coordinates reproductive behavior with ovulation. The primary signal from the central nervous system is gonadotropin-releasing hormone (GnRH), which modulates the activity of anterior pituitary gonadotropes regulating follicle stimulating hormone (FSH) and luteinizing hormone (LH) release. As ovarian follicles develop they release estradiol, which negatively regulates further release of GnRH and FSH. As estradiol concentrations peak they trigger the surge release of GnRH, which leads to LH release inducing ovulation. Release of GnRH within the central nervous system helps modulate reproductive behaviors providing a node at which control of reproduction is regulated. To address these issues, this review focuses on several critical questions. How is the HPG axis regulated in species with different reproductive strategies? What internal and external conditions modulate the synthesis and release of GnRH? How does GnRH modulate reproductive behavior within the hypothalamus? How does disease shift the activity of the HPG axis?

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“…This dose has also been widely reported in studies investigating the mechanism of GnRH (or GnRH-like peptides) (Wu et al, 2009. Lastly, alterations in the expression and activity of the GnRH-cleaving enzyme, EP24.15, may promote the synthesis of GnRH-(1e5) as seen in prostate cancer (Swanson et al, 2004); and in our lab using various endometrial cancer cell lines representative of different stages (unpublished data). Furthermore, EP24.15 cleavage of GnRH to GnRH-(1e5) is enhanced 10-fold upon prolyl endopeptidase-mediated removal of the 10th amino acid (Lew et al, 1994).…”

Section: Discussionmentioning

confidence: 54%

GnRH-(1–5) activates matrix metallopeptidase-9 to release epidermal growth factor and promote cellular invasion

Cho-Clark

Larco

Zahn

et al. 2015

Molecular and Cellular Endocrinology

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In the extracellular space, the gonadotropin-releasing hormone (GnRH) is metabolized by the zinc metalloendopeptidase EC3.4.24.15 (EP24.15) to form the pentapeptide, GnRH-(1-5). GnRH-(1-5) diverges in function and mechanism of action from GnRH in the brain and periphery. GnRH-(1-5) acts on the orphan G protein-coupled receptor 101 (GPR101) to sequentially stimulate epidermal growth factor (EGF) release, phosphorylate the EGF receptor (EGFR), and facilitate cellular migration. These GnRH-(1-5) actions are dependent on matrix metallopeptidase (MMP) activity. Here, we demonstrated that these GnRH-(1-5) effects are dependent on increased MMP-9 enzymatic activity in the Ishikawa and ECC-1 cell lines. Furthermore, the effects of GnRH-(1-5) mediated by GPR101 and the subsequent increase in MMP-9 enzymatic activity lead to an increase in cellular invasion. These results suggest that GnRH-(1-5) and GPR101 regulation of MMP-9 may have physiological relevance in the metastatic potential of endometrial cancer cells.

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The Role of Neuropeptide Processing Enzymes in Endocrine (Prostate) Cancer: EC 3.4.24.15 (EP24.15)

Cited by 16 publications

References 0 publications

Opioid Receptor Function Is Regulated by Post-endocytic Peptide Processing

Opioid Receptor Function Is Regulated by Post-endocytic Peptide Processing

Hormonal Regulation of Female Reproduction

GnRH-(1–5) activates matrix metallopeptidase-9 to release epidermal growth factor and promote cellular invasion

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