Heparin-binding EGF-like growth factor is an autocrine growth factor for human urothelial cells and is synthesized by epithelial and smooth muscle cells in the human bladder

J Clin Invest. 1997 Mar 1;99(5):1028-36. doi: 10.1172/JCI119230.


The epidermal growth factor receptor (HER1) has been implicated in regenerative growth and proliferative diseases of the human bladder epithelium (urothelium), however a cognate HER1 ligand that can act as a growth factor for normal human urothelial cells (HUC) has not been identified. Here we show that heparin-binding EGF-like growth factor (HB-EGF), an activating HER1 ligand, is an autocrine regulator of HUC growth. This conclusion is based on demonstration of HB-EGF synthesis and secretion by primary culture HUC, identification of HER1 as an activatable HB-EGF receptor on HUC surfaces, stimulation of HUC clonal growth by HB-EGF, inhibition of HB-EGF-stimulated growth by heparin and of log-phase growth by CRM 197, a specific inhibitor of HB-EGF/HER1 interaction, and identification of human urothelium as a site of HB-EGF precursor (proHB-EGF) synthesis in vivo. ProHB-EGF expression was also detected in the vascular and detrusor smooth muscle of the human bladder. These data suggest a physiologic role for HB-EGF in the regulation of urothelial proliferation and regeneration subsequent to mucosal injury. Expression of proHB-EGF is also a feature of differentiated vascular and detrusor smooth muscle in the bladder. Because proHB-EGF is known to be the high affinity diphtheria toxin (DT) receptor in human cells, synthesis of the HB-EGF precursor by human urothelium also suggests the possibility of using the DT-binding sites of proHB-EGF as an in vivo target for the intraluminal treatment of urothelial diseases.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Bacterial Proteins / pharmacology
  • Blotting, Northern
  • Blotting, Western
  • Cells, Cultured
  • Child
  • Child, Preschool
  • Chromatography, Affinity
  • Chromatography, High Pressure Liquid
  • Clone Cells / metabolism
  • DNA Probes
  • Diphtheria Toxin / pharmacology
  • Epidermal Growth Factor / immunology
  • Epidermal Growth Factor / metabolism*
  • Epidermal Growth Factor / physiology*
  • Epidermal Growth Factor / therapeutic use
  • ErbB Receptors / metabolism
  • ErbB Receptors / physiology
  • Heparin / metabolism
  • Heparin / pharmacology
  • Humans
  • Immunohistochemistry
  • In Situ Hybridization
  • Muscle, Smooth / cytology
  • Muscle, Smooth / metabolism*
  • Phorbol Esters / pharmacology
  • Phosphorylation
  • RNA / analysis
  • RNA / metabolism
  • Tyrosine / metabolism
  • Urinary Bladder / growth & development*
  • Urinary Bladder / metabolism*
  • Urinary Bladder Diseases / drug therapy
  • Urothelium / cytology
  • Urothelium / growth & development*
  • Urothelium / metabolism*


  • Bacterial Proteins
  • DNA Probes
  • Diphtheria Toxin
  • Phorbol Esters
  • CRM197 (non-toxic variant of diphtheria toxin)
  • Tyrosine
  • Epidermal Growth Factor
  • RNA
  • Heparin
  • ErbB Receptors