Epidermal growth factor receptor regulates pancreatic fibrosis.
The development of pancreatic fibrosis has been shown to be a major component in several diseases of the pancreas including pancreatic cancer, chronic pancreatitis, and type 2 diabetes mellitus, but its actual role in the progression of these disorders is still unknown. This fibrosis is characterized by stromal expansion and the excessive deposition of extracellular matrix (ECM) that replaces pancreatic tissue. This eventually leads to dysregulation of ECM turnover, production of cytokines, restriction of blood flow, and often exocrine and endocrine insufficiencies. Activated pancreatic stellate cells (PSCs) have been identified as key mediators in the progression of pancreatic fibrosis, serving as the predominant source of excess ECM proteins. Previously, we found that overexpression of the growth factor heparin-binding epidermal growth factor-like growth factor (HB-EGF) in pancreatic islets led to intraislet fibrosis. HB-EGF binds to and activates two receptors, epidermal growth factor receptor (EGFR) and ErbB4, as well as heparin moieties and CD9/DRAP27. To understand the mechanism underlying the induction of fibrogenesis by HB-EGF, we utilized a hypomorphic allele of Egfr, the Waved-2 allele, to demonstrate that EGFR signaling regulates fibrogenesis in vivo. Using an in vitro cell migration assay, we show that HB-EGF regulates both chemoattraction and stimulation of proliferation of PSCs via EGFR activation.
Blaine
Stacy A
SA
Department of Surgery, Vanderbilt University, Nashville, Tennessee 37232-0443, USA.
Ray
Kevin C
KC
Branch
Kevin M
KM
Robinson
Pamela S
PS
Whitehead
Robert H
RH
Means
Anna L
AL
D000818:Animals; D002460:Cell Line; D049109:Cell Proliferation; D002633:Chemotaxis; D004195:Disease Models, Animal; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D005355:Fibrosis; D066257:Heparin-binding EGF-like Growth Factor; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation; D010179:Pancreas / Q000378:metabolism* / Q000473:pathology; D010182:Pancreatic Diseases / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D011994:Recombinant Proteins / Q000378:metabolism; D015398:Signal Transduction; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism
C587884:Hbegf protein, mouse; D066257:Heparin-binding EGF-like Growth Factor; D018398:Homeodomain Proteins; D036341:Intercellular Signaling Peptides and Proteins; D011994:Recombinant Proteins; D015534:Trans-Activators; C084010:pancreatic and duodenal homeobox 1 protein; C541485:EGFR protein, mouse; D066246:ErbB Receptors