Involvement of phosphatidylinositol 3-kinase in stromal cell-derived factor-1 alpha-induced lymphocyte polarization and chemotaxis.
The role of phosphatidylinositol 3-kinase (PI3-kinase), an important enzyme involved in signal transduction events, has been studied in the polarization and chemotaxis of lymphocytes induced by the chemokine stromal cell-derived factor-1 alpha (SDF-1 alpha). This chemokine was able to directly activate p85/p110 PI3-kinase in whole human PBL and to induce the association of PI3-kinase to the SDF-1 alpha receptor, CXCR4, in a pertussis toxin-sensitive manner. Two unrelated chemical inhibitors of PI3-kinase, wortmannin and Ly294002, prevented ICAM-3 and ERM protein moesin polarization as well as the chemotaxis of PBL in response to SDF-1 alpha. However, they did not interfere with the reorganization of either tubulin or the actin cytoskeleton. Moreover, the transient expression of a dominant negative form of the PI3-kinase 85-kDa regulatory subunit in the constitutively polarized Peer T cell line inhibited ICAM-3 polarization and markedly reduced SDF-1 alpha-induced chemotaxis. Conversely, overexpression of a constitutively activated mutant of the PI3-kinase 110-kDa catalytic subunit in the round-shaped PM-1 T cell line induced ICAM-3 polarization. These results underline the role of PI3-kinase in the regulation of lymphocyte polarization and motility and indicate that PI3-kinase plays a selective role in the regulation of adhesion and ERM proteins redistribution in the plasma membrane of lymphocytes.
Vicente-Manzanares
M
M
Servicio de Inmunología, Hospital de la Princesa, Universidad Autónoma de Madrid, Spain.
Rey
M
M
Jones
D R
DR
Sancho
D
D
Mellado
M
M
Rodriguez-Frade
J M
JM
del Pozo
M A
MA
Yáñez-Mó
M
M
de Ana
A M
AM
Martínez-A
C
C
Mérida
I
I
Sánchez-Madrid
F
F
D015703:Antigens, CD; D000943:Antigens, Differentiation; D015815:Cell Adhesion Molecules / Q000378:metabolism; D002460:Cell Line; D002465:Cell Movement / Q000276:immunology; D016764:Cell Polarity / Q000235:genetics / Q000276:immunology*; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000502:physiology*; D002634:Chemotaxis, Leukocyte / Q000235:genetics / Q000276:immunology*; D003599:Cytoskeleton / Q000201:enzymology / Q000276:immunology / Q000378:metabolism; D004790:Enzyme Induction / Q000276:immunology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D008840:Microfilament Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D019718:Receptors, CXCR4 / Q000378:metabolism; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000494:pharmacology; D017154:Stromal Cells / Q000201:enzymology / Q000276:immunology; D013601:T-Lymphocytes / Q000166:cytology / Q000201:enzymology* / Q000276:immunology*; D014162:Transfection
D015703:Antigens, CD; D000943:Antigens, Differentiation; D015815:Cell Adhesion Molecules; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; D004791:Enzyme Inhibitors; D008840:Microfilament Proteins; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D019718:Receptors, CXCR4; D011994:Recombinant Proteins; C515255:CXCL12 protein, human; C483616:ICAM3 protein, human; C071058:moesin