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Published 5 December 2005. doi:10.1083/jcb.200509172
The Rockefeller University Press, 0021-9525 $8.00
JCB, Volume 171, Number 5, 871-881
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Article

The Rac activator Tiam1 is required for {alpha}3ß1-mediated laminin-5 deposition, cell spreading, and cell migration



Irene H.L. Hamelers, Cristina Olivo, Alexander E.E. Mertens, D. Michiel Pegtel, Rob A. van der Kammen, Arnoud Sonnenberg, and John G. Collard

Division of Cell Biology, Netherlands Cancer Institute, 1066 CX Amsterdam, Netherlands

Correspondence to John G. Collard: j.collard{at}nki.nl

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 {alpha}3ß1-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 {alpha}3ß1-mediated activation of Rac, which is essential for proper production and secretion of LN5, a requirement for the spreading and migration of keratinocytes.

I.H.L. Hamelers and C. Olivo contributed equally to this paper.

Irene H.L. Hamelers's present address is Dept. of Biochemistry of Membranes, Institute of Biomembranes, Utrecht University, 3584 CH Utrecht, Netherlands.

Cristina Olivo's present address is Dept. of Hematology, University Medical Center Utrecht, 3508 GA Utrecht, Netherlands.

Abbreviations used in this paper: Col IV, collagen IV; ERK, extracellular-signal regulated kinase; FN, fibronectin; GEF, guanine nucleotide exchange factor; LN, laminin; NPAG, p-nitrophenyl N-acetyl-ß-D-glucosaminide; PAK, p21-activated kinase; PLL, poly-L-lysine; Tiam1, T-lymphoma invasion and metastasis 1; Tiam1–/–, Tiam1-deficient; VN, vitronectin; WT, wild-type.


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