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Autocrine epidermal growth factor signaling stimulates directionally persistent mammary epithelial cell migration.

Maheshwari G, Wiley HS, Lauffenburger DA - J. Cell Biol. (2001)

Bottom Line: The possibly diverse effect of presenting a growth factor in autocrine as opposed to exogenous (or paracrine) mode is an especially important issue in cell biology.Addition of exogenous EGF to these cells abrogates their enhanced directional persistence, reducing their directionality to a level similar to wild-type cells.These findings emphasize the functional importance of spatial restriction of EGFR signaling, and suggest critical implications for growth factor-based therapeutic treatments.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.

ABSTRACT
Cell responses to soluble regulatory factors may be strongly influenced by the mode of presentation of the factor, as in matrix-bound versus diffusible modes. The possibly diverse effect of presenting a growth factor in autocrine as opposed to exogenous (or paracrine) mode is an especially important issue in cell biology. We demonstrate here that migration behavior of human mammary epithelial cells in response to stimulation by epidermal growth factor (EGF) is qualitatively different for EGF presented in exogenous (paracrine), autocrine, and intracrine modes. When EGF is added as an exogenous factor to the medium of cells that express EGF receptor (EGFR) but not EGF, cell migration speed increases while directional persistence decreases. When these EGFR-expressing cells are made to also express via retroviral transfection EGF in protease-cleaveable transmembrane form on the plasma membrane, migration speed similarly increases, but directional persistence increases as well. Addition of exogenous EGF to these cells abrogates their enhanced directional persistence, reducing their directionality to a level similar to wild-type cells. If the EGFR-expressing cells are instead transduced with a gene encoding EGF in a soluble form, migration speed and directional persistence were unaffected. Thus, autocrine presentation of EGF at the plasma membrane in a protease-cleavable form provides these cells with an enhanced ability to migrate persistently in a given direction, consistent with their increased capability for organizing into gland-like structures. In contrast, an exogenous/paracrine mode of EGF presentation generates a "scattering" response by the cells. These findings emphasize the functional importance of spatial restriction of EGFR signaling, and suggest critical implications for growth factor-based therapeutic treatments.

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Effect of ligand presentation on cell path length. Path length is the product of cell speed and persistence under a given set of conditions. Filled, hatched, and blank bars represent the cell speeds of EGF-Ct–expressing cells, sEGF-expressing cells, and WT HMEC respectively. Path lengths were calculated in the presence and absence of exogenously added EGF.
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fig5: Effect of ligand presentation on cell path length. Path length is the product of cell speed and persistence under a given set of conditions. Filled, hatched, and blank bars represent the cell speeds of EGF-Ct–expressing cells, sEGF-expressing cells, and WT HMEC respectively. Path lengths were calculated in the presence and absence of exogenously added EGF.

Mentions: The net effect of EGFR-mediated induction of cell migration by the three modes of EGF presentation can be viewed in terms of a quantity reflecting the cell path behavior illustrated in the windrose plots of Fig. 3: the product of migration speed and persistence time is the “mean path length,” plotted in Fig. 5. It is clear that EGF presented in autocrine manner provides HMEC with an ability to migrate for many cell lengths before altering their direction significantly, whereas presentation of EGF in intracrine or paracrine manner yields nondirected migration behavior which should result in cell scattering.


Autocrine epidermal growth factor signaling stimulates directionally persistent mammary epithelial cell migration.

Maheshwari G, Wiley HS, Lauffenburger DA - J. Cell Biol. (2001)

Effect of ligand presentation on cell path length. Path length is the product of cell speed and persistence under a given set of conditions. Filled, hatched, and blank bars represent the cell speeds of EGF-Ct–expressing cells, sEGF-expressing cells, and WT HMEC respectively. Path lengths were calculated in the presence and absence of exogenously added EGF.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2199328&req=5

fig5: Effect of ligand presentation on cell path length. Path length is the product of cell speed and persistence under a given set of conditions. Filled, hatched, and blank bars represent the cell speeds of EGF-Ct–expressing cells, sEGF-expressing cells, and WT HMEC respectively. Path lengths were calculated in the presence and absence of exogenously added EGF.
Mentions: The net effect of EGFR-mediated induction of cell migration by the three modes of EGF presentation can be viewed in terms of a quantity reflecting the cell path behavior illustrated in the windrose plots of Fig. 3: the product of migration speed and persistence time is the “mean path length,” plotted in Fig. 5. It is clear that EGF presented in autocrine manner provides HMEC with an ability to migrate for many cell lengths before altering their direction significantly, whereas presentation of EGF in intracrine or paracrine manner yields nondirected migration behavior which should result in cell scattering.

Bottom Line: The possibly diverse effect of presenting a growth factor in autocrine as opposed to exogenous (or paracrine) mode is an especially important issue in cell biology.Addition of exogenous EGF to these cells abrogates their enhanced directional persistence, reducing their directionality to a level similar to wild-type cells.These findings emphasize the functional importance of spatial restriction of EGFR signaling, and suggest critical implications for growth factor-based therapeutic treatments.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.

ABSTRACT
Cell responses to soluble regulatory factors may be strongly influenced by the mode of presentation of the factor, as in matrix-bound versus diffusible modes. The possibly diverse effect of presenting a growth factor in autocrine as opposed to exogenous (or paracrine) mode is an especially important issue in cell biology. We demonstrate here that migration behavior of human mammary epithelial cells in response to stimulation by epidermal growth factor (EGF) is qualitatively different for EGF presented in exogenous (paracrine), autocrine, and intracrine modes. When EGF is added as an exogenous factor to the medium of cells that express EGF receptor (EGFR) but not EGF, cell migration speed increases while directional persistence decreases. When these EGFR-expressing cells are made to also express via retroviral transfection EGF in protease-cleaveable transmembrane form on the plasma membrane, migration speed similarly increases, but directional persistence increases as well. Addition of exogenous EGF to these cells abrogates their enhanced directional persistence, reducing their directionality to a level similar to wild-type cells. If the EGFR-expressing cells are instead transduced with a gene encoding EGF in a soluble form, migration speed and directional persistence were unaffected. Thus, autocrine presentation of EGF at the plasma membrane in a protease-cleavable form provides these cells with an enhanced ability to migrate persistently in a given direction, consistent with their increased capability for organizing into gland-like structures. In contrast, an exogenous/paracrine mode of EGF presentation generates a "scattering" response by the cells. These findings emphasize the functional importance of spatial restriction of EGFR signaling, and suggest critical implications for growth factor-based therapeutic treatments.

Show MeSH
Related in: MedlinePlus