OPRPN

OPRPN (BPLP/PROL1) encodes a proline-rich secreted protein expressed abundantly in lacrimal gland secretory endpieces and, more weakly, in the submandibular gland (PMID:8670737). The protein is proteolytically processed in vivo to the opiorphin pentapeptide (QRFSR), which is detectable in human saliva (PMID:22119435) and functions as an endogenous neutral endopeptidase (NEP) inhibitor (PMID:18410445). Through this activity, opiorphin influences physiological signaling in two arenas: in erectile physiology, intracorporal ProL1 gene transfer raises resting intracavernous pressure and improves the ICP/BP ratio (PMID:18410445), and in systemic blood pressure regulation, intravenous opiorphin dose-dependently raises mean arterial pressure with elevated serum angiotensin II, an effect blocked by the AngII receptor antagonist valsartan and attenuated by ACE inhibition, placing it upstream of the renin-angiotensin system (PMID:24486428). Independently of its secreted peptide role, OPRPN is required for prostate cancer tumorigenicity: knockout in LNCaP cells abolishes xenograft tumor formation while overexpression enables tumor growth in castrated mice and increases cell motility and invasion, accompanied by transcriptional remodeling of angiogenesis, motility, steroid, and hypoxic-response gene pathways (PMID:33593085, PMID:35547856).

1. 1996 Medium

   Established the molecular identity of OPRPN as a proline-rich secreted protein and localized its expression to exocrine gland secretory tissue, defining it as a candidate secretory product.

   Evidence cDNA cloning, Northern blot, and in situ hybridization in human lacrimal and submandibular gland

   PMID:8670737

   Open questions at the time

   • Function of the full-length protein not addressed
   • No characterization of post-translational processing into bioactive fragments
2. 2008 Medium

   Linked OPRPN/ProL1 to erectile physiology by showing in vivo that its gene transfer alters cavernous pressure, and proposed it acts as a NEP inhibitor.

   Evidence Intracorporal pVAX-ProL1 gene transfer in rats with intracavernous pressure measurement; expression downregulated in human ED tissue

   PMID:18410445

   Open questions at the time

   • No in vitro reconstitution of NEP inhibition for ProL1 itself
   • Expression downregulation in ED is correlative
   • Molecular target prolonged by NEP inhibition not directly identified
3. 2009 Low

   Articulated the mechanistic model that the opiorphin peptide inhibits NEP to prolong peptide agonist action at GPCRs, using rat orthologs.

   Evidence Organ bath corporal smooth muscle relaxation assay with sialorphin and in vitro GPCR expression studies with Vcsa1 (rat orthologs)

   PMID:19267851

   Open questions at the time

   • ProL1/OPRPN itself not directly tested for NEP inhibition in this work
   • Inference rests on rat ortholog behavior
   • Specific GPCRs and peptide agonists involved not defined
4. 2011 Medium

   Confirmed that the OPRPN-encoded protein is processed to the mature opiorphin pentapeptide in humans by detecting and quantifying it in saliva.

   Evidence LC-MS/MS quantification of opiorphin in human saliva

   PMID:22119435

   Open questions at the time

   • Processing enzymes generating opiorphin not identified
   • Physiological concentration at sites of action not established
5. 2014 Medium

   Placed opiorphin upstream of the renin-angiotensin system in blood pressure control through pharmacological epistasis.

   Evidence In vivo rat cannulation with valsartan and captopril blockade and serum AngII ELISA

   PMID:24486428

   Open questions at the time

   • Direct molecular link between NEP inhibition and AngII elevation not resolved
   • Single species and single lab
6. 2021 Medium

   Revealed a cell-autonomous oncogenic role distinct from the secreted-peptide function, showing OPRPN is necessary and sufficient for prostate cancer xenograft growth and drives invasion.

   Evidence Overexpression and CRISPR knockout in LNCaP cells, xenograft assays in castrated and intact mice, wound closure and 3D spheroid invasion assays, RNAseq

   PMID:33593085 PMID:35547856

   Open questions at the time

   • Molecular mechanism connecting OPRPN to angiogenesis/motility transcriptional changes unknown
   • Whether the effect requires opiorphin processing or full-length protein not determined
   • Single cell line and single lab
7. 2023 Low

   Positioned Prol1 expression as a target of BMP-2/Smad signaling during salivary gland development.

   Evidence Organ culture of embryonic mouse salivary glands with BMP-2 treatment and dorsomorphin rescue (ortholog)

   PMID:37742472

   Open questions at the time

   • Prol1 measured as a readout; its functional role in acinar differentiation not established
   • Mouse ortholog in organ culture only
8. 2024 Low

   Connected Prol1 expression to TGF-β1/SMAD2/3 signaling in submandibular gland epithelial development.

   Evidence Ex vivo epithelia-mesenchyme separation organ culture with TGF-β1, microarray, qRT-PCR, Western blot (ortholog)

   PMID:39040362

   Open questions at the time

   • Prol1 is one correlative readout among many genes
   • No direct functional experiment on Prol1 protein
   • Mouse ortholog only

• Whether the secreted opiorphin/NEP-inhibitor activity and the cell-autonomous oncogenic role in prostate cancer share a common molecular mechanism, and the direct NEP-inhibition kinetics of the human peptide, remain unresolved.
• No biochemical reconstitution of human opiorphin NEP inhibition
• No mechanistic link between secreted-peptide function and intracellular tumor-promoting function
• No structural model of the protein or peptide-target complex