Rho GTPases control migration and polarization of adhesion molecules and cytoskeletal ERM components in T lymphocytes.
Motile lymphocytes adopt a polarized morphology with different adhesion molecules (ICAM, CD43 and CD44) and ERM actin-binding proteins concentrated on the uropod, a slender posterior appendage with important functions in cell-cell interactions and lymphocyte recruitment. We have studied the role of Rho family of GTPases (Rho, Rac and Cdc42) in the control of lymphocyte polarity and migration by analyzing the effects of exogenously introduced Rho GTPase mutants. Transfection of T cell lines that constitutively display a polarized motile morphology with activated mutants of RhoA, Rac1 and Cdc42 impaired cell polarization. A guanosine nucleotide exchange factor for Rac, Tiam-1, induced the same effect as activated Rac1. Conversely, dominant negative forms of the three GTP-binding proteins induced a polarized phenotype in constitutively round-shaped T cells with redistribution of ICAM-3 and moesin to the uropod in an integrin-dependent manner. On the other hand, overexpression of dominant negative Cdc42 and activated mutants of all three Rho GTPases significantly inhibited SDF-1alpha-induced T cell chemotaxis. Together, these data demonstrate that Rho GTPases regulate lymphocyte polarization and chemokine-induced migration, and underscore the key role of Cdc42 in lymphocyte directional migration.
del Pozo
M A
MA
Servicio de Inmunología, Hospital de la Princesa, Universidad Autónoma de Madrid, Madrid, Spain. mdelpozo@scripps.edu
Vicente-Manzanares
M
M
Tejedor
R
R
Serrador
J M
JM
Sánchez-Madrid
F
F
D015703:Antigens, CD; D000943:Antigens, Differentiation; D015815:Cell Adhesion Molecules / Q000378:metabolism*; D002460:Cell Line; D016764:Cell Polarity / Q000502:physiology*; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; D002633:Chemotaxis / Q000502:physiology*; D003599:Cytoskeleton; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism; D025581:Neurofibromin 2; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D013601:T-Lymphocytes / Q000502:physiology*; D000075684:T-Lymphoma Invasion and Metastasis-inducing Protein 1; D020764:cdc42 GTP-Binding Protein / Q000235:genetics / Q000378:metabolism*; D020830:rac1 GTP-Binding Protein / Q000235:genetics / Q000378:metabolism*; D020742:rhoA GTP-Binding Protein / Q000235:genetics / Q000378:metabolism*
D015703:Antigens, CD; D000943:Antigens, Differentiation; C515255:CXCL12 protein, human; D015815:Cell Adhesion Molecules; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; D020662:Guanine Nucleotide Exchange Factors; C483616:ICAM3 protein, human; D008565:Membrane Proteins; D025581:Neurofibromin 2; D011506:Proteins; D000075684:T-Lymphoma Invasion and Metastasis-inducing Protein 1; C087334:TIAM1 protein, human; D020764:cdc42 GTP-Binding Protein; D020830:rac1 GTP-Binding Protein; D020742:rhoA GTP-Binding Protein