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The Rac activator Tiam1 is required for (alpha)3(beta)1-mediated laminin-5 deposition, cell spreading, and cell migration.

Hamelers IH, Olivo C, Mertens AE, Pegtel DM, van der Kammen RA, Sonnenberg A, Collard JG - J. Cell Biol. (2005)

Bottom Line: Both Tiam1 and V12Rac1 can rescue the defects of Tiam1-/- keratinocytes, indicating that these deficiencies are caused by impaired Tiam1-mediated Rac activation.Moreover, Tiam1 deficiency impairs keratinocyte migration in vitro and reepithelialization of excision wounds in mouse skin.Our studies indicate that Tiam1 is a key molecule in alpha3beta1-mediated activation of Rac, which is essential for proper production and secretion of LN5, a requirement for the spreading and migration of keratinocytes.

View Article: PubMed Central - PubMed

Affiliation: Division of Cell Biology, Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands.

ABSTRACT
The Rho-like guanosine triphosphatase Rac1 regulates various signaling pathways, including integrin-mediated adhesion and migration of cells. However, the mechanisms by which integrins signal toward Rac are poorly understood. We show that the Rac-specific guanine nucleotide exchange factor Tiam1 (T-lymphoma invasion and metastasis 1) is required for the integrin-mediated laminin (LN)-5 deposition, spreading, and migration of keratinocytes. In contrast to wild-type keratinocytes, Tiam1-deficient (Tiam1-/-) keratinocytes are unable to adhere to and spread on a glass substrate because they are unable to deposit their own LN5 substrate. Both Tiam1 and V12Rac1 can rescue the defects of Tiam1-/- keratinocytes, indicating that these deficiencies are caused by impaired Tiam1-mediated Rac activation. Tiam1-/- cells are unable to activate Rac upon alpha3beta1-mediated adhesion to an exogenous LN5 substrate. Moreover, Tiam1 deficiency impairs keratinocyte migration in vitro and reepithelialization of excision wounds in mouse skin. Our studies indicate that Tiam1 is a key molecule in alpha3beta1-mediated activation of Rac, which is essential for proper production and secretion of LN5, a requirement for the spreading and migration of keratinocytes.

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Model of the function of Tiam1 in keratinocyte adhesion to and spreading on an inert substrate. (1) Upon touching the surface, WT cells secrete small amounts of LN5. (2) The cells bind the LN5 with their LN5 integrin (α3β1) and signal to Tiam1, which is necessary for Rac activation and actin remodeling. (3) Tiam1-mediated Rac activation and actin polymerization are required for increased LN5 production, LN5 vesicle secretion, and cell spreading. (1') Tiam1−/− cells secrete small amounts of LN5 upon touching an inert surface. (2') Cells fail to activate Rac through the α3β1 integrin as a result of Tiam1 deficiency. (3') Consequently, Tiam1−/− cells are unable to produce and secrete proper amounts of additional LN5 and, therefore, cell spreading and cell migration is impaired.
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fig10: Model of the function of Tiam1 in keratinocyte adhesion to and spreading on an inert substrate. (1) Upon touching the surface, WT cells secrete small amounts of LN5. (2) The cells bind the LN5 with their LN5 integrin (α3β1) and signal to Tiam1, which is necessary for Rac activation and actin remodeling. (3) Tiam1-mediated Rac activation and actin polymerization are required for increased LN5 production, LN5 vesicle secretion, and cell spreading. (1') Tiam1−/− cells secrete small amounts of LN5 upon touching an inert surface. (2') Cells fail to activate Rac through the α3β1 integrin as a result of Tiam1 deficiency. (3') Consequently, Tiam1−/− cells are unable to produce and secrete proper amounts of additional LN5 and, therefore, cell spreading and cell migration is impaired.

Mentions: Tiam1-Rac signaling has been shown to control various processes in epithelial cells, such as cell migration, by affecting E-cadherin–based adhesions (Sander and Collard, 1999; Malliri and Collard, 2003; Minard et al., 2004), and cell polarization, by affecting tight junction biogenesis (Mertens et al., 2005). We have investigated the role of Tiam1-Rac signaling in the adhesion and spreading of mouse keratinocytes. We found that Tiam1−/− keratinocytes adhere to and spread on various exogenous cell substrates, but do not spread on uncoated surfaces such as glass, on which these cells have to make their own LN5 substrate. Both Tiam1 and V12Rac1 can rescue the adhesion and spreading defect of Tiam1−/− keratinocytes on glass, indicating that this defect is the result of impaired Rac signaling. Our studies indicate that Tiam1 is a key molecule in α3β1-mediated activation of Rac, which is required for LN5 production and secretion. We propose that Tiam1 regulates α3β1-mediated Rac activation upon initial adhesion, which controls actin remodeling and increased LN5 production and secretion, which are all necessary for the spreading and migration of keratinocytes (Fig. 10).


The Rac activator Tiam1 is required for (alpha)3(beta)1-mediated laminin-5 deposition, cell spreading, and cell migration.

Hamelers IH, Olivo C, Mertens AE, Pegtel DM, van der Kammen RA, Sonnenberg A, Collard JG - J. Cell Biol. (2005)

Model of the function of Tiam1 in keratinocyte adhesion to and spreading on an inert substrate. (1) Upon touching the surface, WT cells secrete small amounts of LN5. (2) The cells bind the LN5 with their LN5 integrin (α3β1) and signal to Tiam1, which is necessary for Rac activation and actin remodeling. (3) Tiam1-mediated Rac activation and actin polymerization are required for increased LN5 production, LN5 vesicle secretion, and cell spreading. (1') Tiam1−/− cells secrete small amounts of LN5 upon touching an inert surface. (2') Cells fail to activate Rac through the α3β1 integrin as a result of Tiam1 deficiency. (3') Consequently, Tiam1−/− cells are unable to produce and secrete proper amounts of additional LN5 and, therefore, cell spreading and cell migration is impaired.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2171282&req=5

fig10: Model of the function of Tiam1 in keratinocyte adhesion to and spreading on an inert substrate. (1) Upon touching the surface, WT cells secrete small amounts of LN5. (2) The cells bind the LN5 with their LN5 integrin (α3β1) and signal to Tiam1, which is necessary for Rac activation and actin remodeling. (3) Tiam1-mediated Rac activation and actin polymerization are required for increased LN5 production, LN5 vesicle secretion, and cell spreading. (1') Tiam1−/− cells secrete small amounts of LN5 upon touching an inert surface. (2') Cells fail to activate Rac through the α3β1 integrin as a result of Tiam1 deficiency. (3') Consequently, Tiam1−/− cells are unable to produce and secrete proper amounts of additional LN5 and, therefore, cell spreading and cell migration is impaired.
Mentions: Tiam1-Rac signaling has been shown to control various processes in epithelial cells, such as cell migration, by affecting E-cadherin–based adhesions (Sander and Collard, 1999; Malliri and Collard, 2003; Minard et al., 2004), and cell polarization, by affecting tight junction biogenesis (Mertens et al., 2005). We have investigated the role of Tiam1-Rac signaling in the adhesion and spreading of mouse keratinocytes. We found that Tiam1−/− keratinocytes adhere to and spread on various exogenous cell substrates, but do not spread on uncoated surfaces such as glass, on which these cells have to make their own LN5 substrate. Both Tiam1 and V12Rac1 can rescue the adhesion and spreading defect of Tiam1−/− keratinocytes on glass, indicating that this defect is the result of impaired Rac signaling. Our studies indicate that Tiam1 is a key molecule in α3β1-mediated activation of Rac, which is required for LN5 production and secretion. We propose that Tiam1 regulates α3β1-mediated Rac activation upon initial adhesion, which controls actin remodeling and increased LN5 production and secretion, which are all necessary for the spreading and migration of keratinocytes (Fig. 10).

Bottom Line: Both Tiam1 and V12Rac1 can rescue the defects of Tiam1-/- keratinocytes, indicating that these deficiencies are caused by impaired Tiam1-mediated Rac activation.Moreover, Tiam1 deficiency impairs keratinocyte migration in vitro and reepithelialization of excision wounds in mouse skin.Our studies indicate that Tiam1 is a key molecule in alpha3beta1-mediated activation of Rac, which is essential for proper production and secretion of LN5, a requirement for the spreading and migration of keratinocytes.

View Article: PubMed Central - PubMed

Affiliation: Division of Cell Biology, Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands.

ABSTRACT
The Rho-like guanosine triphosphatase Rac1 regulates various signaling pathways, including integrin-mediated adhesion and migration of cells. However, the mechanisms by which integrins signal toward Rac are poorly understood. We show that the Rac-specific guanine nucleotide exchange factor Tiam1 (T-lymphoma invasion and metastasis 1) is required for the integrin-mediated laminin (LN)-5 deposition, spreading, and migration of keratinocytes. In contrast to wild-type keratinocytes, Tiam1-deficient (Tiam1-/-) keratinocytes are unable to adhere to and spread on a glass substrate because they are unable to deposit their own LN5 substrate. Both Tiam1 and V12Rac1 can rescue the defects of Tiam1-/- keratinocytes, indicating that these deficiencies are caused by impaired Tiam1-mediated Rac activation. Tiam1-/- cells are unable to activate Rac upon alpha3beta1-mediated adhesion to an exogenous LN5 substrate. Moreover, Tiam1 deficiency impairs keratinocyte migration in vitro and reepithelialization of excision wounds in mouse skin. Our studies indicate that Tiam1 is a key molecule in alpha3beta1-mediated activation of Rac, which is essential for proper production and secretion of LN5, a requirement for the spreading and migration of keratinocytes.

Show MeSH
Related in: MedlinePlus