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Matrix stiffening sensitizes epithelial cells to EGF and enables the loss of contact inhibition of proliferation
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| Zeitschriftentitel: | Journal of Cell Science |
|---|---|
| Personen und Körperschaften: | , |
| In: | Journal of Cell Science, 124, 2011, 8, S. 1280-1287 |
| Format: | E-Article |
| Sprache: | Englisch |
| veröffentlicht: |
The Company of Biologists
|
| Schlagwörter: |
| author_facet |
Kim, Jin-Hong Asthagiri, Anand R. Kim, Jin-Hong Asthagiri, Anand R. |
|---|---|
| author |
Kim, Jin-Hong Asthagiri, Anand R. |
| spellingShingle |
Kim, Jin-Hong Asthagiri, Anand R. Journal of Cell Science Matrix stiffening sensitizes epithelial cells to EGF and enables the loss of contact inhibition of proliferation Cell Biology |
| author_sort |
kim, jin-hong |
| spelling |
Kim, Jin-Hong Asthagiri, Anand R. 1477-9137 0021-9533 The Company of Biologists Cell Biology http://dx.doi.org/10.1242/jcs.078394 <jats:p>Anchorage to a compliant extracellular matrix (ECM) and contact with neighboring cells impose important constraints on the proliferation of epithelial cells. How anchorage and contact dependence are inter-related and how cells weigh these adhesive cues alongside soluble growth factors to make a net cell cycle decision remain unclear. Here, we show that a moderate 4.5-fold stiffening of the matrix reduces the threshold amount of epidermal growth factor (EGF) needed to over-ride contact inhibition by over 100-fold. At EGF doses in the range of the dissociation constant (Kd) for ligand binding, epithelial cells on soft matrices are contact inhibited with DNA synthesis restricted to the periphery of cell clusters. By contrast, on stiff substrates, even EGF doses at sub-Kd levels over-ride contact inhibition, leading to proliferation throughout the cluster. Thus, matrix stiffening significantly sensitizes cells to EGF, enabling contact-independent spatially uniform proliferation. Contact inhibition on soft substrates requires E-cadherin, and the loss of contact inhibition upon matrix stiffening is accompanied by the disruption of cell–cell contacts, changes in the localization of the EGF receptor and ZO-1, and selective attenuation of ERK, but not Akt, signaling. We propose a quantitative framework for the epigenetic priming (via ECM stiffening) of a classical oncogenic pathway (EGF) with implications for the regulation of tissue growth during morphogenesis and cancer progression.</jats:p> Matrix stiffening sensitizes epithelial cells to EGF and enables the loss of contact inhibition of proliferation Journal of Cell Science |
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| title |
Matrix stiffening sensitizes epithelial cells to EGF and enables the loss of contact inhibition of proliferation |
| title_unstemmed |
Matrix stiffening sensitizes epithelial cells to EGF and enables the loss of contact inhibition of proliferation |
| title_full |
Matrix stiffening sensitizes epithelial cells to EGF and enables the loss of contact inhibition of proliferation |
| title_fullStr |
Matrix stiffening sensitizes epithelial cells to EGF and enables the loss of contact inhibition of proliferation |
| title_full_unstemmed |
Matrix stiffening sensitizes epithelial cells to EGF and enables the loss of contact inhibition of proliferation |
| title_short |
Matrix stiffening sensitizes epithelial cells to EGF and enables the loss of contact inhibition of proliferation |
| title_sort |
matrix stiffening sensitizes epithelial cells to egf and enables the loss of contact inhibition of proliferation |
| topic |
Cell Biology |
| url |
http://dx.doi.org/10.1242/jcs.078394 |
| publishDate |
2011 |
| physical |
1280-1287 |
| description |
<jats:p>Anchorage to a compliant extracellular matrix (ECM) and contact with neighboring cells impose important constraints on the proliferation of epithelial cells. How anchorage and contact dependence are inter-related and how cells weigh these adhesive cues alongside soluble growth factors to make a net cell cycle decision remain unclear. Here, we show that a moderate 4.5-fold stiffening of the matrix reduces the threshold amount of epidermal growth factor (EGF) needed to over-ride contact inhibition by over 100-fold. At EGF doses in the range of the dissociation constant (Kd) for ligand binding, epithelial cells on soft matrices are contact inhibited with DNA synthesis restricted to the periphery of cell clusters. By contrast, on stiff substrates, even EGF doses at sub-Kd levels over-ride contact inhibition, leading to proliferation throughout the cluster. Thus, matrix stiffening significantly sensitizes cells to EGF, enabling contact-independent spatially uniform proliferation. Contact inhibition on soft substrates requires E-cadherin, and the loss of contact inhibition upon matrix stiffening is accompanied by the disruption of cell–cell contacts, changes in the localization of the EGF receptor and ZO-1, and selective attenuation of ERK, but not Akt, signaling. We propose a quantitative framework for the epigenetic priming (via ECM stiffening) of a classical oncogenic pathway (EGF) with implications for the regulation of tissue growth during morphogenesis and cancer progression.</jats:p> |
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| author | Kim, Jin-Hong, Asthagiri, Anand R. |
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| description | <jats:p>Anchorage to a compliant extracellular matrix (ECM) and contact with neighboring cells impose important constraints on the proliferation of epithelial cells. How anchorage and contact dependence are inter-related and how cells weigh these adhesive cues alongside soluble growth factors to make a net cell cycle decision remain unclear. Here, we show that a moderate 4.5-fold stiffening of the matrix reduces the threshold amount of epidermal growth factor (EGF) needed to over-ride contact inhibition by over 100-fold. At EGF doses in the range of the dissociation constant (Kd) for ligand binding, epithelial cells on soft matrices are contact inhibited with DNA synthesis restricted to the periphery of cell clusters. By contrast, on stiff substrates, even EGF doses at sub-Kd levels over-ride contact inhibition, leading to proliferation throughout the cluster. Thus, matrix stiffening significantly sensitizes cells to EGF, enabling contact-independent spatially uniform proliferation. Contact inhibition on soft substrates requires E-cadherin, and the loss of contact inhibition upon matrix stiffening is accompanied by the disruption of cell–cell contacts, changes in the localization of the EGF receptor and ZO-1, and selective attenuation of ERK, but not Akt, signaling. We propose a quantitative framework for the epigenetic priming (via ECM stiffening) of a classical oncogenic pathway (EGF) with implications for the regulation of tissue growth during morphogenesis and cancer progression.</jats:p> |
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| spelling | Kim, Jin-Hong Asthagiri, Anand R. 1477-9137 0021-9533 The Company of Biologists Cell Biology http://dx.doi.org/10.1242/jcs.078394 <jats:p>Anchorage to a compliant extracellular matrix (ECM) and contact with neighboring cells impose important constraints on the proliferation of epithelial cells. How anchorage and contact dependence are inter-related and how cells weigh these adhesive cues alongside soluble growth factors to make a net cell cycle decision remain unclear. Here, we show that a moderate 4.5-fold stiffening of the matrix reduces the threshold amount of epidermal growth factor (EGF) needed to over-ride contact inhibition by over 100-fold. At EGF doses in the range of the dissociation constant (Kd) for ligand binding, epithelial cells on soft matrices are contact inhibited with DNA synthesis restricted to the periphery of cell clusters. By contrast, on stiff substrates, even EGF doses at sub-Kd levels over-ride contact inhibition, leading to proliferation throughout the cluster. Thus, matrix stiffening significantly sensitizes cells to EGF, enabling contact-independent spatially uniform proliferation. Contact inhibition on soft substrates requires E-cadherin, and the loss of contact inhibition upon matrix stiffening is accompanied by the disruption of cell–cell contacts, changes in the localization of the EGF receptor and ZO-1, and selective attenuation of ERK, but not Akt, signaling. We propose a quantitative framework for the epigenetic priming (via ECM stiffening) of a classical oncogenic pathway (EGF) with implications for the regulation of tissue growth during morphogenesis and cancer progression.</jats:p> Matrix stiffening sensitizes epithelial cells to EGF and enables the loss of contact inhibition of proliferation Journal of Cell Science |
| spellingShingle | Kim, Jin-Hong, Asthagiri, Anand R., Journal of Cell Science, Matrix stiffening sensitizes epithelial cells to EGF and enables the loss of contact inhibition of proliferation, Cell Biology |
| title | Matrix stiffening sensitizes epithelial cells to EGF and enables the loss of contact inhibition of proliferation |
| title_full | Matrix stiffening sensitizes epithelial cells to EGF and enables the loss of contact inhibition of proliferation |
| title_fullStr | Matrix stiffening sensitizes epithelial cells to EGF and enables the loss of contact inhibition of proliferation |
| title_full_unstemmed | Matrix stiffening sensitizes epithelial cells to EGF and enables the loss of contact inhibition of proliferation |
| title_short | Matrix stiffening sensitizes epithelial cells to EGF and enables the loss of contact inhibition of proliferation |
| title_sort | matrix stiffening sensitizes epithelial cells to egf and enables the loss of contact inhibition of proliferation |
| title_unstemmed | Matrix stiffening sensitizes epithelial cells to EGF and enables the loss of contact inhibition of proliferation |
| topic | Cell Biology |
| url | http://dx.doi.org/10.1242/jcs.078394 |