Trafficking of nuclear heparin-binding epidermal growth factor-like growth factor into an epidermal growth factor receptor-dependent autocrine loop in response to oxidative stress.
Heparin-binding epidermal growth factor (EGF)-like growth factor (HB-EGF) accumulates in the nucleus in aggressive transitional cell carcinoma (TCC) cells and this histologic feature is a marker of poor prognosis in human bladder cancer tissues. Here we report that HB-EGF can be exported from the nucleus during stimulated processing and secretion of the growth factor. Production of reactive oxygen species (ROS) resulted in mobilization of the HB-EGF precursor, proHB-EGF, from the nucleus of TCCSUP bladder cancer cells to a detergent-resistant membrane compartment, where the growth factor was cleaved by a metalloproteinase-mediated mechanism and shed into the extracellular space. Inhibition of nuclear export suppressed HB-EGF shedding. Production of ROS resulted in EGF receptor (EGFR) and Akt1 phosphorylation in HB-EGF-expressing cells. HB-EGF also stimulated cell proliferation and conferred cytoprotection when cells were challenged with cisplatin. These findings show that the nucleus can serve as an intracellular reservoir for a secreted EGFR ligand and, thus, can contribute to an autocrine loop leading to cell proliferation and protection from apoptotic stimuli.
Kim
Jayoung
J
The Urological Diseases Research Center, Childrens Hospital, Boston, Massachusetts, USA.
Adam
Rosalyn M
RM
Freeman
Michael R
MR
D021581:Active Transport, Cell Nucleus / Q000502:physiology; D017209:Apoptosis / Q000502:physiology; D002295:Carcinoma, Transitional Cell / Q000378:metabolism*; D048708:Cell Growth Processes / Q000502:physiology; D002467:Cell Nucleus / Q000378:metabolism*; D004815:Epidermal Growth Factor / Q000378:metabolism*; D066246:ErbB Receptors / Q000378:metabolism*; D005434:Flow Cytometry; D066257:Heparin-binding EGF-like Growth Factor; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D018384:Oxidative Stress; D011498:Protein Precursors / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D001749:Urinary Bladder Neoplasms / Q000378:metabolism*
C587883:HBEGF protein, human; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins; D011498:Protein Precursors; D017382:Reactive Oxygen Species; D004815:Epidermal Growth Factor; D066246:ErbB Receptors