Signaling mechanisms of inhibition of phospholipase D activation by CHS-111 in formyl peptide-stimulated neutrophils

被引:17
作者
Chang, Ling-Chu [2 ]
Huang, Tai-Hung [3 ]
Chang, Chi-Sen [4 ]
Tsai, Ya-Ru [1 ]
Lin, Ruey-Hseng [2 ,5 ]
Lee, Pin-Wen [3 ]
Hsu, Mei-Feng [6 ]
Huang, Li-Jiau [3 ]
Wang, Jih-Pyang [1 ,3 ]
机构
[1] Taichung Vet Gen Hosp, Dept Med Res, Taichung 407, Taiwan
[2] Chung Shan Med Univ, Inst Med, Taichung, Taiwan
[3] China Med Univ, Grad Inst Pharmaceut Chem, Taichung, Taiwan
[4] Taichung Vet Gen Hosp, Div Gastroenterol & Hepatol, Taichung 407, Taiwan
[5] Chung Shan Med Univ, Dept Pharmacol, Taichung, Taiwan
[6] China Med Univ, Dept Biochem, Taichung, Taiwan
关键词
CHS-111; Phospholipase D; RhoA; Arf6; Protein kinase C; Vav; Neutrophils; PROTEIN-KINASE-C; ADP-RIBOSYLATION-FACTOR; SRC FAMILY KINASES; TYROSINE PHOSPHORYLATION; LEUCYL-PHENYLALANINE; RESPIRATORY BURST; STRUCTURAL BASIS; RAT NEUTROPHILS; PLASMA-MEMBRANE; RHO-FAMILY;
D O I
10.1016/j.bcp.2010.10.007
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
A selective phospholipase D (PLO) inhibitor 5-fluoro-2-indolyl des-chlorohalopemide (FIPI) inhibited the O-2(center dot-) generation and cell migration but not degranulation in formyl-Met-Leu-Phe(fMLP)-stimulated rat neutrophils. A novel benzyl indazole compound 2-benzyl-3-(4-hydroxymethylphenyl)indazole (CHS-111), which inhibited O-2(center dot-) generation and cell migration, also reduced the fMLP- but not phorbol ester-stimulated PLO activity (IC50 3.9 +/- 1.2 mu M). CHS-111 inhibited the interaction of PLD1 with ADP-ribosylation factor (Art) 6 and Ras homology (Rho) A, and reduced the membrane recruitment of RhoA in fMLP-stimulated cells but not in GTP gamma S-stimulated cell-free system. CHS-111 reduced the cellular levels of GTP-bound RhoA, membrane recruitment of Rho-associated protein kinase 1 and the downstream myosin light chain 2 phosphorylation, and attenuated the interaction between phosphatidylinositol 4-phosphate 5-kinase (PIP5K) and Arf6, whereas it only slightly inhibited the guanine nucleotide exchange activity of human Dbs (DH/PH) protein and did not affect the arfaptin binding to Arf6. CHS-111 inhibited the interaction of RhoA with Vav, the membrane association and the phosphorylation of Vav. CHS-111 had no effect on the phosphorylation of Src family kinases (SFK) but attenuated the interaction of Vav with Lck, Hck, Fgr and Lyn. CHS-111 also inhibited the interaction of PLD1 with protein kinase C (PKC)alpha, beta I and beta II isoenzymes, and the phosphorylation of PLD1. These results indicate that inhibition of fMLP-stimulated PLO activity by CHS-111 is attributable to the blockade of RhoA activation via the interference with SFK-mediated Vav activation, attenuation of the interaction of Arf6 with PLD1 and PIP5K, and the activation of Ca2+-dependent PKC in rat neutrophils. (C) 2010 Elsevier Inc. All rights reserved.
引用
收藏
页码:269 / 278
页数:10
相关论文
共 34 条
[1]   Structural basis for relief of autoinhibition of the Dbl homology domain of proto-oncogene Vav by tyrosine phosphorylation [J].
Aghazadeh, B ;
Lowry, WE ;
Huang, XY ;
Rosen, MK .
CELL, 2000, 102 (05) :625-633
[2]  
Berton G, 1999, Curr Opin Hematol, V6, P51, DOI 10.1097/00062752-199901000-00009
[3]   Inhibition of superoxide anion generation by CHS-111 via blockade of the p21-activated kinase, protein kinase B/Akt and protein kinase C signaling pathways in rat neutrophils [J].
Chang, Ling-Chu ;
Lin, Ruey-Hseng ;
Huang, Li-Jiau ;
Chang, Chi-Sen ;
Kuo, Sheng-Chu ;
Wang, Jih-Pyang .
EUROPEAN JOURNAL OF PHARMACOLOGY, 2009, 615 (1-3) :207-217
[4]   Cytohesin-1 Regulates the Arf6-Phospholipase D Signaling Axis in Human Neutrophils: Impact on Superoxide Anion Production and Secretion [J].
El Azreq, Mohammed-Amine ;
Garceau, Valerie ;
Harbour, Danielle ;
Pivot-Pajot, Christophe ;
Bourgoin, Sylvain G. .
JOURNAL OF IMMUNOLOGY, 2010, 184 (02) :637-649
[5]   The Src family kinases Hck and Fgr regulate neutrophil responses to N-formyl-methionyl-leucyl-phenylalanine [J].
Fumagalli, Laura ;
Zhang, Hong ;
Baruzzi, Anna ;
Lowell, Clifford A. ;
Berton, Giorgio .
JOURNAL OF IMMUNOLOGY, 2007, 178 (06) :3874-3885
[6]   Activation mechanisms of PIP5K isozymes by the small GTPase ARF6 [J].
Funakoshi, Yuji ;
Hasegawa, Hiroshi ;
Kanaho, Yasunori .
ADVANCES IN ENZYME REGULATION, VOL 50, 2010, 50 :72-+
[7]   Understanding phospholipase D (PLD) using leukocytes: PLD involvement in cell adhesion and chemotaxis [J].
Gomez-Cambronero, Julian ;
Di Fulvio, Mauricio ;
Knapek, Katie .
JOURNAL OF LEUKOCYTE BIOLOGY, 2007, 82 (02) :272-281
[8]   Characterization of two alternately spliced forms of phospholipase D1 - Activation of the purified enzymes by phosphatidylinositol 4,5-bisphosphate, ADP-ribosylation factor, and RHO family monomeric GTP-binding proteins and protein kinase C-alpha [J].
Hammond, SM ;
Jenco, JM ;
Nakashima, S ;
Cadwallader, K ;
Gu, QM ;
Cook, S ;
Nozawa, Y ;
Prestwich, GD ;
Frohman, MA ;
Morris, AJ .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1997, 272 (06) :3860-3868
[9]   Lck regulates Vav activation of members of the Rho family of GTPases [J].
Han, JW ;
Das, B ;
Wei, W ;
VanAelst, L ;
Mosteller, RD ;
Khosravifar, R ;
Westwick, JK ;
Der, CJ ;
Broek, D .
MOLECULAR AND CELLULAR BIOLOGY, 1997, 17 (03) :1346-1353
[10]   PLATELET-DERIVED GROWTH-FACTOR STIMULATES SYNTHESIS OF PTDLNS(3,4,5)P3 BY ACTIVATING A PTDLNS(4,5)P2 3-OH KINASE [J].
HAWKINS, PT ;
JACKSON, TR ;
STEPHENS, LR .
NATURE, 1992, 358 (6382) :157-159