The Rac activator Tiam1 is required for (alpha)3(beta)1-mediated laminin-5 deposition, cell spreading, and cell migration.
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.
Hamelers
Irene H L
IH
Division of Cell Biology, Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands.
Olivo
Cristina
C
Mertens
Alexander E E
AE
Pegtel
D Michiel
DM
van der Kammen
Rob A
RA
Sonnenberg
Arnoud
A
Collard
John G
JG
D000818:Animals; D002448:Cell Adhesion; D015815:Cell Adhesion Molecules / Q000378:metabolism*; D002465:Cell Movement; D048430:Cell Shape; D002478:Cells, Cultured; D024141:Collagen Type IV / Q000378:metabolism; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000502:physiology*; D039201:Integrin alpha3beta1 / Q000502:physiology*; D015603:Keratinocytes / Q000502:physiology; D051379:Mice; D009154:Mutation; D009363:Neoplasm Proteins / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction; D012867:Skin / Q000166:cytology / Q000378:metabolism; D000075684:T-Lymphoma Invasion and Metastasis-inducing Protein 1; D014945:Wound Healing; D020830:rac1 GTP-Binding Protein / Q000378:metabolism*; D000097794:Kalinin
D015815:Cell Adhesion Molecules; D024141:Collagen Type IV; D020662:Guanine Nucleotide Exchange Factors; D039201:Integrin alpha3beta1; D009363:Neoplasm Proteins; D000075684:T-Lymphoma Invasion and Metastasis-inducing Protein 1; D020830:rac1 GTP-Binding Protein; D000097794:Kalinin; C513260:Tiam1 protein, mouse