Abstract
In MDCK cells, hepatocyte growth factor/scatter factor (HGF/SF) induces epithelial cell dissociation, scattering, migration, growth and formation of branched tubular structures. By contrast, these cells neither scatter nor form tubular structures in response to the epidermal growth factor (EGF) family of growth factors. Heparin-binding EGF-like growth factor (HB-EGF) is a member of the EGF family of growth factors and is synthesized as a membrane-associated precursor molecule (proHB-EGF). ProHB-EGF is proteolytically cleaved to release a soluble ligand (sHB-EGF) that activates the EGF receptor. Although recent studies suggest possible physiological functions, the role of proHB-EGF remains largely undefined. Using MDCK cells stably expressing proHB-EGF, a noncleavable deletion mutant of proHB-EGF or soluble HB-EGF, we show that epithelial cell functions differ depending on the form of HB-EGF being expressed. Expression of noncleavable membrane-anchored HB-EGF promoted cell-matrix and cell-cell interactions and decreased cell migration, HGF/SF-induced cell scattering and formation of tubular structures. By contrast, expression of soluble HB-EGF induced increased cell migration, decreased cell-matrix and cell-cell interactions and promoted the development of long unbranched tubular structures in response to HGF/SF. These findings suggest that HB-EGF can not only modulate HGF/SF-induced cellular responses in MDCK cells but also that membrane-bound HB-EGF and soluble HB-EGF give rise to distinctly different effects on cell-cell and cell-extracellular matrix interactions.
Highlights
The maintenance of the structural and functional integrity of epithelia requires highly dynamic cell-cell and cell-matrix interactions
We show that expression of membrane-bound HB-epidermal growth factor (EGF) inhibits hepatocyte growth factor/scatter factor (HGF/SF)-induced cell scattering and formation of branched tubular structures
To differentiate between effects mediated by the membrane-anchored and soluble forms of HB- EGF, we developed stably transfected renal epithelial cells (MDCK II cells) expressing soluble HBEGF, proHB-EGF and deletion mutant constructs of proHB-EGF lacking the amino terminal 5 (MDCK5aa) and 12 amino acids (MDCK12aa) of the juxtamembrane extracellular domain (Fig. 1)
Summary
The maintenance of the structural and functional integrity of epithelia requires highly dynamic cell-cell and cell-matrix interactions. In addition to causing proliferation, HGF/SF induces normal epithelial cells grown on plastic to ‘scatter’ because of increased motility and reduced cell-cell interactions and results in cells growing as a dispersed culture in carcinoma cells, where invasiveness is increased by HGF/SF (Bardelli et al, 1997; Maulik et al, 2002). Exogenous epidermal growth factor (EGF) induces DNA synthesis and cell proliferation in MDCK cells (Hauguel-DeMouzon et al, 1992), it does not induce scattering or branching tubulogenesis (Tanimura et al, 1998), nor does it modulate the response of HGF/SF (Liang and Chen, 2001; Tanimura et al, 1998)
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