Sequential Regulation of DOCK2 Dynamics by Two Phospholipids During Neutrophil Chemotaxis

Nishikimi, Akihiko; Fukuhara, Hideo; Su, Wenjuan; Hongu, Tsunaki; Takasuga, Shunsuke; Mihara, Hisashi; Cao, Qinhong; Sanematsu, Fumiyuki; Kanai, Motomu; Hasegawa, Hiroshi; Tanaka, Yoshihiko; Shibasaki, Masakatsu; Kanaho, Yasunori; Sasaki, Takehiko; Frohman, Michael A.; Fukui, Yoshihiro

doi:10.1126/science.1170179

Cited by 250 publications

(234 citation statements)

References 24 publications

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“…Although both ANCA IgG and fMLF are able to induce PA generation, it is likely that these are indicative of two separate pools with distinct properties. For example, PA generated through the actions of PLD may have roles in chemotaxis and modulation of the actin cytoskeleton (50,51), whereas it is evident from work here that the actions of DGK activated by ANCA IgG ligation do not modulate the actin cytoskeleton. We have previously documented the importance of the PI3K pathway in promoting ANCA-induced neutrophil activation (11), and this is likely to be central in promoting changes to the actin cytoskeleton (52).…”

Section: +contrasting

confidence: 40%

A Dual Role for Diacylglycerol Kinase Generated Phosphatidic Acid in Autoantibody-Induced Neutrophil Exocytosis

Holden

Savage

Young

et al. 2011

Mol Med

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Section: +contrasting

confidence: 40%

A Dual Role for Diacylglycerol Kinase Generated Phosphatidic Acid in Autoantibody-Induced Neutrophil Exocytosis

Holden

Savage

Young

et al. 2011

Mol Med

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“…However, in addition to the P-Rex and Vav families, which both belong to the Dbl superfamily, neutrophils also express DOCK2, a Rac-GEF from the structurally unrelated DOCK superfamily (41). The mechanisms regulating DOCK2 activity in neutrophils are unknown, but DOCK2 membrane translocation (which is required for function) is known to depend on PIP 3 and phosphatidic acid formation (42,43). GPCRstimulated DOCK2 2/2 neutrophils can sense chemoattractant gradients but migrate with reduced speed, lack the polarized accumulation of F-actin and PIP 3 at the leading edge, and show substantially reduced Rac1 and Rac2 activity (42).…”

Section: Discussionmentioning

confidence: 99%

P-Rex1 and Vav1 Cooperate in the Regulation of Formyl-Methionyl-Leucyl-Phenylalanine–Dependent Neutrophil Responses

Lawson

Donald

Anderson

et al. 2011

The Journal of Immunology

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G protein-coupled receptor (GPCR) activation elicits neutrophil responses such as chemotaxis and reactive oxygen species (ROS) formation, which depend on the small G protein Rac and are essential for host defense. P-Rex and Vav are two families of guanine-nucleotide exchange factors (GEFs) for Rac, which are activated through distinct mechanisms but can both control GPCR-dependent neutrophil responses. It is currently unknown whether they play specific roles or whether they can compensate for each other in controlling these responses. In this study, we have assessed the function of neutrophils from mice deficient in P-Rex and/or Vav family GEFs. We found that both the P-Rex and the Vav family are important for LPS priming of ROS formation, whereas particle-induced ROS responses and cell spreading are controlled by the Vav family alone. Surprisingly, fMLF-stimulated ROS formation, adhesion, and chemotaxis were synergistically controlled by P-Rex1 and Vav1. These responses were more severely impaired in neutrophils lacking both P-Rex1 and Vav1 than those lacking the entire P-Rex family, the entire Vav family, or both P-Rex1 and Vav3. P-Rex1/Vav1 (P1V1) double-deficient cells also showed the strongest reduction in fMLF-stimulated activation of Rac1 and Rac2. This reduction in Rac activity may be sufficient to cause the defects observed in fMLF-stimulated P1V1 neutrophil responses. Additionally, Mac-1 surface expression was reduced in P1V1 cells, which might contribute further to defects in responses involving integrins, such as GPCR-stimulated adhesion and chemotaxis. We conclude that P-Rex1 and Vav1 together are the major fMLFR -dependent Dbl family Rac-GEFs in neutrophils and cooperate in the control of fMLF-stimulated neutrophil responses.

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“…phates, followed by polybasic region binding to phosphatidic acid (36). Further studies are required to expose whether localization of DOCK180 can be regulated in a similar manner.…”

Section: Discussionmentioning

confidence: 99%

The Arf Family GTPase Arl4A Complexes with ELMO Proteins to Promote Actin Cytoskeleton Remodeling and Reveals a Versatile Ras-binding Domain in the ELMO Proteins Family

Patel

Chiang

Tran

et al. 2011

Journal of Biological Chemistry

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Background: ELMO complexes with DOCK180 and contributes to Rac signaling. Results: Arl4A binds ELMO and is a membrane localization signal that triggers DOCK180-Rac-dependent actin cytoskeleton remodeling. Conclusion: ELMO, via its versatile Ras-binding domain, binds its effector Arl4A, and this novel interaction facilitates Rac signaling. Significance: This is the first demonstration of a Ras-binding domain that binds Arf or Rho family GTPases.

show abstract

Sequential Regulation of DOCK2 Dynamics by Two Phospholipids During Neutrophil Chemotaxis

Cited by 250 publications

References 24 publications

A Dual Role for Diacylglycerol Kinase Generated Phosphatidic Acid in Autoantibody-Induced Neutrophil Exocytosis

A Dual Role for Diacylglycerol Kinase Generated Phosphatidic Acid in Autoantibody-Induced Neutrophil Exocytosis

P-Rex1 and Vav1 Cooperate in the Regulation of Formyl-Methionyl-Leucyl-Phenylalanine–Dependent Neutrophil Responses

The Arf Family GTPase Arl4A Complexes with ELMO Proteins to Promote Actin Cytoskeleton Remodeling and Reveals a Versatile Ras-binding Domain in the ELMO Proteins Family

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