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Originally published online as doi:10.1189/jlb.0907664 on May 1, 2008

Published online before print May 1, 2008
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(Journal of Leukocyte Biology. 2008;84:255-263.)
© 2008 by Society for Leukocyte Biology

Calpain-mediated regulation of the distinct signaling pathways and cell migration in human neutrophils

Masataka Katsube, Takayuki Kato, Maki Kitagawa, Haruyoshi Noma, Hisakazu Fujita and Seiichi Kitagawa1

Department of Physiology, Osaka City University Graduate School of Medicine, Osaka, Japan

1Correspondence: Department of Physiology, Osaka City University Graduate School of Medicine, Asahi-machi, Abeno-ku, Osaka 545-8585, Japan. E-mail: kitagawas{at}med.osaka-cu.ac.jp

We studied the mechanisms underlying calpain inhibition-mediated human neutrophil migration. MAPKs, including ERK, p38, and JNK, MEK1/2, MAPK kinase 3/6 (MKK3/6), PI-3K/Akt, c-Raf, and p21-activated kinase (PAK; an effector molecule of Rac) were rapidly (within 30 s) activated in neutrophils upon exposure to calpain inhibitors (PD150606 and N-acetyl-Leu-Leu-Nle-CHO) but not PD145305 (inactive analog of PD150606). Following activation of these pathways, neutrophils displayed active migration (chemotaxis), which was sustained for more than 45 min. The studies with pharmacological inhibitors suggest that calpain inhibition-mediated neutrophil migration is mediated by activation of MEK/ERK, p38, JNK, PI-3K/Akt, and Rac. NSC23766 (Rac inhibitor) and pertussis toxin (PTX) suppressed calpain inhibitor-induced phosphorylation of distinct signaling molecules (PAK, c-Raf, MEK1/2, ERK, MKK3/6, p38, JNK, and Akt) as well as cell migration, suggesting that the PTX-sensitive G protein and Rac axis may be a possible key target of calpain inhibitors. Differentiated neutrophil-like HL-60 cells but not undifferentiated cells displayed cell migration and activation of MAPKs and PI-3K/Akt on calpain inhibition. These findings suggest that constitutively active calpain negatively regulates activation of the distinct signaling pathways and cell migration in resting neutrophils, and this regulatory system develops during differentiation into mature neutrophils.

Key Words: mitogen-activated protein kinases • pertussis toxin • phosphatidylinositol 3-kinase • Rac




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