U73122 inhibits the dephosphorylation and translocation of cofilin in activated macrophage-like U937 cells.
Cofilin, an actin-binding protein, plays an important role in the migration, phagocytosis, and superoxide production of activated phagocytes through cytoskeletal reorganization. In unstimulated phagocytes, cofilin is a major phosphoprotein. However, upon activation, the phosphoprotein is dephosphorylated and translocated from cytosol to plasma membranes. Only the unphosphorylated form of cofilin is an active form that binds actin, whereas the regulatory mechanisms of cofilin have not been elucidated. We found that 1-[6-[[17beta-3-methoxyestra-1,3,5(10)-trien-17-yl]amino]hexyl]-1H-pyrrole-2,5-dione (U73122), an inhibitor of phospholipase C (PLC), suppressed both opsonized zymosan (OZ)-induced dephosphorylation and translocation of cofilin in macrophage-like U937 cells at 4 microM concentration. OZ triggered an increase in inositol 1,4,5-trisphosphate (IP3), and U73122 inhibited it. 1-[6-[[17beta-3-Methoxyestra-1,3,5(10)-trien-17-yl]amino]hexyl]-1H-pyrrole-2,5-pyrrodione-dione (U73343), which was employed as an inactive analogue, had no such inhibitory activities as did U73122. Furthermore, herbimycin A, an inhibitor of src-type tyrosine kinase, also inhibited OZ-triggered IP3 formation. These results suggest that the activity and localization of cofilin are regulated by PLC at the downstream of src-family tyrosine kinase.
Matsui
S
S
National Institute of Health Sciences, 1-18-1 Kamiyoga 1-chome, Setagaya-ku, 158, Tokyo, Japan.
Adachi
R
R
Kusui
K
K
Yamaguchi
T
T
Kasahara
T
T
Hayakawa
T
T
Suzuki
K
K
D051339:Actin Depolymerizing Factors; D002462:Cell Membrane / Q000378:metabolism; D004963:Estrenes / Q000378:metabolism* / Q000494:pharmacology; D018922:HL-60 Cells; D006801:Humans; D066298:In Vitro Techniques; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism; D008262:Macrophage Activation; D008840:Microfilament Proteins / Q000378:metabolism*; D009895:Opsonin Proteins; D010766:Phosphorylation; D021381:Protein Transport / Q000502:physiology*; D011760:Pyrrolidinones / Q000378:metabolism* / Q000494:pharmacology; D013481:Superoxides / Q000378:metabolism; D010738:Type C Phospholipases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D020298:U937 Cells; D015054:Zymosan; D019061:src-Family Kinases / Q000378:metabolism
D051339:Actin Depolymerizing Factors; D004963:Estrenes; D008840:Microfilament Proteins; D009895:Opsonin Proteins; D011760:Pyrrolidinones; D013481:Superoxides; C060229:1-(6-((3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl)-1H-pyrrole-2,5-dione; C074854:U 73343; D015544:Inositol 1,4,5-Trisphosphate; D015054:Zymosan; D019061:src-Family Kinases; D010738:Type C Phospholipases