Qinhong Cao

Publications (3)51.58 Total impact

• Article: Blockade of inflammatory responses by a small-molecule inhibitor of the Rac activator DOCK2.

  Akihiko Nishikimi, Takehito Uruno, Xuefeng Duan, Qinhong Cao, Yuji Okamura, Takashi Saitoh, Nae Saito, Shunsuke Sakaoka, Yao Du, Atsushi Suenaga, [......], Takayoshi Okabe, Fumiyuki Sanematsu, Yoshihiko Tanaka, Hideki Sumimoto, Teruki Honma, Shigeyuki Yokoyama, Tetsuo Nagano, Daisuke Kohda, Motomu Kanai, Yoshinori Fukui
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  ABSTRACT: Tissue infiltration of activated lymphocytes is a hallmark of transplant rejection and organ-specific autoimmune diseases. Migration and activation of lymphocytes depend on DOCK2, an atypical Rac activator predominantly expressed in hematopoietic cells. Although DOCK2 does not contain Dbl homology domain typically found in guanine nucleotide exchange factors, DOCK2 mediates the GTP-GDP exchange reaction for Rac through its DHR-2 domain. Here, we have identified 4-[3'-(2″-chlorophenyl)-2'-propen-1'-ylidene]-1-phenyl-3,5-pyrazolidinedione (CPYPP) as a small-molecule inhibitor of DOCK2. CPYPP bound to DOCK2 DHR-2 domain in a reversible manner and inhibited its catalytic activity in vitro. When lymphocytes were treated with CPYPP, both chemokine receptor- and antigen receptor-mediated Rac activation were blocked, resulting in marked reduction of chemotactic response and T cell activation. These results provide a rational of and a chemical scaffold for development of the DOCK2-targeting immunosuppressant.
  Chemistry & biology 04/2012; 19(4):488-97. · 6.52 Impact Factor
• Source

  Available from: Yoshinori Fukui

  Article: Selective control of type I IFN induction by the Rac activator DOCK2 during TLR-mediated plasmacytoid dendritic cell activation.

  Kazuhito Gotoh, Yoshihiko Tanaka, Akihiko Nishikimi, Risa Nakamura, Hisakata Yamada, Naoyoshi Maeda, Takahiro Ishikawa, Katsuaki Hoshino, Takehito Uruno, Qinhong Cao, Sadayuki Higashi, Yasushi Kawaguchi, Munechika Enjoji, Ryoichi Takayanagi, Tsuneyasu Kaisho, Yasunobu Yoshikai, Yoshinori Fukui
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  ABSTRACT: Plasmacytoid dendritic cells (pDCs) play a key role in antiviral immunity, but also contribute to the pathogenesis of certain autoimmune diseases, by producing large amounts of type I IFNs. Although activation of pDCs is triggered by engagement of nucleotide-sensing toll-like receptors (TLR) 7 and 9, type I IFN induction additionally requires IkappaB kinase (IKK) alpha-dependent activation of IFN regulatory factor (IRF) 7. However, the signaling pathway mediating IKK-alpha activation is poorly defined. We show that DOCK2, an atypical Rac activator, is essential for TLR7- and TLR9-mediated IFN-alpha induction in pDCs. We found that the exposure of pDCs to nucleic acid ligands induces Rac activation through a TLR-independent and DOCK2-dependent mechanism. Although this Rac activation was dispensable for induction of inflammatory cytokines, phosphorylation of IKK-alpha and nuclear translocation of IRF-7 were impaired in Dock2-deficient pDCs, resulting in selective loss of IFN-alpha induction. Similar results were obtained when a dominant-negative Rac mutant was expressed in wild-type pDCs. Thus, the DOCK2-Rac signaling pathway acts in parallel with TLR engagement to control IKK-alpha activation for type I IFN induction. Owing to its hematopoietic cell-specific expression, DOCK2 may serve as a therapeutic target for type I IFN-related autoimmune diseases.
  Journal of Experimental Medicine 03/2010; 207(4):721-30. · 13.85 Impact Factor
• Article: Sequential regulation of DOCK2 dynamics by two phospholipids during neutrophil chemotaxis.

  Akihiko Nishikimi, Hideo Fukuhara, Wenjuan Su, Tsunaki Hongu, Shunsuke Takasuga, Hisashi Mihara, Qinhong Cao, Fumiyuki Sanematsu, Motomu Kanai, Hiroshi Hasegawa, Yoshihiko Tanaka, Masakatsu Shibasaki, Yasunori Kanaho, Takehiko Sasaki, Michael A Frohman, Yoshinori Fukui
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  ABSTRACT: During chemotaxis, activation of the small guanosine triphosphatase Rac is spatially regulated to organize the extension of membrane protrusions in the direction of migration. In neutrophils, Rac activation is primarily mediated by DOCK2, an atypical guanine nucleotide exchange factor. Upon stimulation, we found that DOCK2 rapidly translocated to the plasma membrane in a phosphatidylinositol 3,4,5-trisphosphate-dependent manner. However, subsequent accumulation of DOCK2 at the leading edge required phospholipase D-mediated synthesis of phosphatidic acid, which stabilized DOCK2 there by means of interaction with a polybasic amino acid cluster, resulting in increased local actin polymerization. When this interaction was blocked, neutrophils failed to form leading edges properly and exhibited defects in chemotaxis. Thus, intracellular DOCK2 dynamics are sequentially regulated by distinct phospholipids to localize Rac activation during neutrophil chemotaxis.
  Science 04/2009; 324(5925):384-7. · 31.20 Impact Factor