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Integrins control motile strategy through a Rho-cofilin pathway.

Danen EH, van Rheenen J, Franken W, Huveneers S, Sonneveld P, Jalink K, Sonnenberg A - J. Cell Biol. (2005)

Bottom Line: During wound healing, angiogenesis, and tumor invasion, cells often change their expression profiles of fibronectin-binding integrins.The activity of the small GTPase RhoA is particularly high in cells adhering by alpha5beta1, and inhibition of Rho signaling causes a switch from a beta1- to a beta3-associated mode of migration, whereas increased Rho activity has the opposite effect.Thus, alterations in integrin expression profiles allow cells to modulate several critical aspects of the motile machinery through Rho GTPases.

View Article: PubMed Central - PubMed

Affiliation: Division of Cell Biology, Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands. e.danen@nki.nl

ABSTRACT
During wound healing, angiogenesis, and tumor invasion, cells often change their expression profiles of fibronectin-binding integrins. Here, we show that beta1 integrins promote random migration, whereas beta3 integrins promote persistent migration in the same epithelial cell background. Adhesion to fibronectin by alpha(v)beta3 supports extensive actin cytoskeletal reorganization through the actin-severing protein cofilin, resulting in a single broad lamellipod with static cell-matrix adhesions at the leading edge. Adhesion by alpha5beta1 instead leads to the phosphorylation/inactivation of cofilin, and these cells fail to polarize their cytoskeleton but extend thin protrusions containing highly dynamic cell-matrix adhesions in multiple directions. The activity of the small GTPase RhoA is particularly high in cells adhering by alpha5beta1, and inhibition of Rho signaling causes a switch from a beta1- to a beta3-associated mode of migration, whereas increased Rho activity has the opposite effect. Thus, alterations in integrin expression profiles allow cells to modulate several critical aspects of the motile machinery through Rho GTPases.

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Model for the control of cell migration by integrin-specific regulation of Rho GTPases. Adhesion by β1 integrins promotes strong Rho/Rho kinase signaling. This counteracts three important parameters of persistent cell migration: (1) Rac-mediated lamellipodia formation; (2) development of static cell–matrix adhesions; and (3) cofilin-mediated actin cytoskeletal reorganization. As a result, β1 integrins promote a random mode of migration. Inhibition of Rho/Rho kinase signaling relieves the suppression of all three aspects and causes a switch from β1- to β3-associated behavior. Conversely, increased Rho signaling in cells adhering by αvβ3 triggers a conversion to β1-associated behavior. Increased Rac signaling can also stimulate a partial conversion from β1- to β3-associated behavior with increased lamellipodia formation and stabilization of cell–matrix adhesions. However, this does not lead to increased cofilin activity and hence, does not stimulate persistence.
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fig7: Model for the control of cell migration by integrin-specific regulation of Rho GTPases. Adhesion by β1 integrins promotes strong Rho/Rho kinase signaling. This counteracts three important parameters of persistent cell migration: (1) Rac-mediated lamellipodia formation; (2) development of static cell–matrix adhesions; and (3) cofilin-mediated actin cytoskeletal reorganization. As a result, β1 integrins promote a random mode of migration. Inhibition of Rho/Rho kinase signaling relieves the suppression of all three aspects and causes a switch from β1- to β3-associated behavior. Conversely, increased Rho signaling in cells adhering by αvβ3 triggers a conversion to β1-associated behavior. Increased Rac signaling can also stimulate a partial conversion from β1- to β3-associated behavior with increased lamellipodia formation and stabilization of cell–matrix adhesions. However, this does not lead to increased cofilin activity and hence, does not stimulate persistence.

Mentions: We show that αvβ3-mediated adhesion to FN supports high cofilin activity, which plays a permissive role in the F-actin cytoskeletal reorganization induced by wounding or by other stimuli such as PMA treatment. This allows for the cytoskeletal polarization observed in persistently migrating cells, with a single broad lamellipod at the leading edge under which cell–matrix adhesions are relatively static. By contrast, cofilin activity is low, polarization does not occur, and cell–matrix adhesions are highly dynamic in cells adhering by α5β1, leading to a random mode of migration. We show that integrin-specific regulation of Rho GTPases underlies the distinct modes of migration: inhibition of Rho signaling promotes membrane ruffling, cofilin-mediated actin cytoskeletal polarization, and cell–matrix adhesion stability and hence, can cause a conversion from β1- to β3-associated migratory behavior. Increased Rac activity promotes membrane ruffling but does not increase cofilin activity, and therefore causes only a partial conversion from β1- to β3-like migration (Fig. 7).


Integrins control motile strategy through a Rho-cofilin pathway.

Danen EH, van Rheenen J, Franken W, Huveneers S, Sonneveld P, Jalink K, Sonnenberg A - J. Cell Biol. (2005)

Model for the control of cell migration by integrin-specific regulation of Rho GTPases. Adhesion by β1 integrins promotes strong Rho/Rho kinase signaling. This counteracts three important parameters of persistent cell migration: (1) Rac-mediated lamellipodia formation; (2) development of static cell–matrix adhesions; and (3) cofilin-mediated actin cytoskeletal reorganization. As a result, β1 integrins promote a random mode of migration. Inhibition of Rho/Rho kinase signaling relieves the suppression of all three aspects and causes a switch from β1- to β3-associated behavior. Conversely, increased Rho signaling in cells adhering by αvβ3 triggers a conversion to β1-associated behavior. Increased Rac signaling can also stimulate a partial conversion from β1- to β3-associated behavior with increased lamellipodia formation and stabilization of cell–matrix adhesions. However, this does not lead to increased cofilin activity and hence, does not stimulate persistence.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2171933&req=5

fig7: Model for the control of cell migration by integrin-specific regulation of Rho GTPases. Adhesion by β1 integrins promotes strong Rho/Rho kinase signaling. This counteracts three important parameters of persistent cell migration: (1) Rac-mediated lamellipodia formation; (2) development of static cell–matrix adhesions; and (3) cofilin-mediated actin cytoskeletal reorganization. As a result, β1 integrins promote a random mode of migration. Inhibition of Rho/Rho kinase signaling relieves the suppression of all three aspects and causes a switch from β1- to β3-associated behavior. Conversely, increased Rho signaling in cells adhering by αvβ3 triggers a conversion to β1-associated behavior. Increased Rac signaling can also stimulate a partial conversion from β1- to β3-associated behavior with increased lamellipodia formation and stabilization of cell–matrix adhesions. However, this does not lead to increased cofilin activity and hence, does not stimulate persistence.
Mentions: We show that αvβ3-mediated adhesion to FN supports high cofilin activity, which plays a permissive role in the F-actin cytoskeletal reorganization induced by wounding or by other stimuli such as PMA treatment. This allows for the cytoskeletal polarization observed in persistently migrating cells, with a single broad lamellipod at the leading edge under which cell–matrix adhesions are relatively static. By contrast, cofilin activity is low, polarization does not occur, and cell–matrix adhesions are highly dynamic in cells adhering by α5β1, leading to a random mode of migration. We show that integrin-specific regulation of Rho GTPases underlies the distinct modes of migration: inhibition of Rho signaling promotes membrane ruffling, cofilin-mediated actin cytoskeletal polarization, and cell–matrix adhesion stability and hence, can cause a conversion from β1- to β3-associated migratory behavior. Increased Rac activity promotes membrane ruffling but does not increase cofilin activity, and therefore causes only a partial conversion from β1- to β3-like migration (Fig. 7).

Bottom Line: During wound healing, angiogenesis, and tumor invasion, cells often change their expression profiles of fibronectin-binding integrins.The activity of the small GTPase RhoA is particularly high in cells adhering by alpha5beta1, and inhibition of Rho signaling causes a switch from a beta1- to a beta3-associated mode of migration, whereas increased Rho activity has the opposite effect.Thus, alterations in integrin expression profiles allow cells to modulate several critical aspects of the motile machinery through Rho GTPases.

View Article: PubMed Central - PubMed

Affiliation: Division of Cell Biology, Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands. e.danen@nki.nl

ABSTRACT
During wound healing, angiogenesis, and tumor invasion, cells often change their expression profiles of fibronectin-binding integrins. Here, we show that beta1 integrins promote random migration, whereas beta3 integrins promote persistent migration in the same epithelial cell background. Adhesion to fibronectin by alpha(v)beta3 supports extensive actin cytoskeletal reorganization through the actin-severing protein cofilin, resulting in a single broad lamellipod with static cell-matrix adhesions at the leading edge. Adhesion by alpha5beta1 instead leads to the phosphorylation/inactivation of cofilin, and these cells fail to polarize their cytoskeleton but extend thin protrusions containing highly dynamic cell-matrix adhesions in multiple directions. The activity of the small GTPase RhoA is particularly high in cells adhering by alpha5beta1, and inhibition of Rho signaling causes a switch from a beta1- to a beta3-associated mode of migration, whereas increased Rho activity has the opposite effect. Thus, alterations in integrin expression profiles allow cells to modulate several critical aspects of the motile machinery through Rho GTPases.

Show MeSH
Related in: MedlinePlus