The RacGEF Tiam1 inhibits migration and invasion of metastatic melanoma via a novel adhesive mechanism.
Rho-like GTPases such as RhoA, Rac1 and Cdc42 are key regulators of actin-dependent cell functions including cell morphology, adhesion and migration. Tiam1 (T lymphoma invasion and metastasis 1), a guanine nucleotide exchange factor that activates Rac, is an important regulator of cell shape and invasiveness in epithelial cells and fibroblasts. Overexpression of Tiam1 in metastatic melanoma cells converted the constitutive mesenchymal phenotype into an epithelial-like phenotype. This included the induction of stringent cell-cell contacts mediated by the Ig-like receptor ALCAM (activated leukocyte cell adhesion molecule) and actin redistribution to cell-cell junctions. This phenotypic switch was dependent on increased Rac but not Rho activity, and on the redistribution and adhesive function of ALCAM, whereas cadherins were not involved. Although cell proliferation was significantly enhanced, the gain of cell-cell junctions strongly counteracted cell motility and invasion as shown for two- and three-dimensional collagen assays as well as invasion into human skin reconstructs. The reverse transition from mesenchymal invasive to a resident epithelial-like phenotype implicates a role for Tiam1/Rac signaling in the control of cell-cell contacts through a novel ALCAM-mediated mechanism.
Uhlenbrock
Katharina
K
Department of Structural Biology, Max-Planck-Institute of Molecular Physiology, Otto-Hahn-Strasse 11, 44227 Dortmund, Germany.
Eberth
Alexander
A
Herbrand
Ulrike
U
Daryab
Neda
N
Stege
Patricia
P
Meier
Friedegund
F
Friedl
Peter
P
Collard
John G
JG
Ahmadian
Mohammad Reza
MR
D020410:Activated-Leukocyte Cell Adhesion Molecule / Q000378:metabolism; D000818:Animals; D002448:Cell Adhesion / Q000502:physiology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology*; D049109:Cell Proliferation; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism*; D006801:Humans; D008545:Melanoma / Q000378:metabolism* / Q000473:pathology*; D009361:Neoplasm Invasiveness; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D000075684:T-Lymphoma Invasion and Metastasis-inducing Protein 1
D020410:Activated-Leukocyte Cell Adhesion Molecule; D020662:Guanine Nucleotide Exchange Factors; D011506:Proteins; D011993:Recombinant Fusion Proteins; D000075684:T-Lymphoma Invasion and Metastasis-inducing Protein 1; C087334:TIAM1 protein, human