Neutrophil direction sensing and superoxide production linked by the GTPase-activating protein GIT2

Mazaki, Yuichi; Hashimoto, Shigeru; Tsujimura, Tohru; Morishige, Masaki; Hashimoto, Ari; Aritake, Kosuke; Yamada, Atsuko; Nam, Jin-Min; Kanazawa, Hiroshi; Nakao, Kazuki; Sabe, Hisataka

doi:10.1038/ni1349

Cited by 73 publications

(82 citation statements)

References 48 publications

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“…Three distinct lines of global GIT1-knockout mice have poor post-natal survival (Pang et al, 2009;Schmalzigaug et al, 2009a;Won et al, 2011), whereas two distinct strains of mice lacking GIT2 survive normally (Mazaki et al, 2006;Schmalzigaug et al, 2009b). β-PIX knockout mice exhibit embryonic lethality (Omelchenko et al, 2014), whereas α-PIXdeficient mice survive normally (Missy et al, 2008).…”

Section: Git Proteinsmentioning

confidence: 99%

“…GIT and PIX can be phosphorylated by PAK (Shin et al, 2002;Webb et al, 2006;Rennefahrt et al, 2007). These multiple feedback loops may amplify local Rac1-and Cdc42-PAK signaling in complex ways (Li et al, 2003;Feng et al, 2006;Mazaki et al, 2006). Furthermore, whereas GIT-PIX has been reported to scaffold many signaling molecules, it remains unclear which partners bind simultaneously and may be able to function together.…”

Section: Git Proteinsmentioning

confidence: 99%

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Expanding functions of GIT Arf GTPase-activating proteins, PIX Rho guanine nucleotide exchange factors and GIT–PIX complexes

Weiyuan

Premont

2016

Journal of Cell Science

100

130

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The GIT proteins, GIT1 and GIT2, are GTPase-activating proteins (inactivators) for the ADP-ribosylation factor (Arf ) small GTP-binding proteins, and function to limit the activity of Arf proteins. The PIX proteins, α-PIX and β-PIX (also known as ARHGEF6 and ARHGEF7, respectively), are guanine nucleotide exchange factors (activators) for the Rho family small GTP-binding protein family members Rac1 and Cdc42. Through their multi-domain structures, GIT and PIX proteins can also function as signaling scaffolds by binding to numerous protein partners. Importantly, the constitutive association of GIT and PIX proteins into oligomeric GIT-PIX complexes allows these two proteins to function together as subunits of a larger structure that coordinates two distinct small GTP-binding protein pathways and serves as multivalent scaffold for the partners of both constituent subunits. Studies have revealed the involvement of GIT and PIX proteins, and of the GIT-PIX complex, in numerous fundamental cellular processes through a wide variety of mechanisms, pathways and signaling partners. In this Commentary, we discuss recent findings in key physiological systems that exemplify current understanding of the function of this important regulatory complex. Further, we draw attention to gaps in crucial information that remain to be filled to allow a better understanding of the many roles of the GIT-PIX complex in health and disease.

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Section: Git Proteinsmentioning

confidence: 99%

Section: Git Proteinsmentioning

confidence: 99%

Expanding functions of GIT Arf GTPase-activating proteins, PIX Rho guanine nucleotide exchange factors and GIT–PIX complexes

Weiyuan

Premont

2016

Journal of Cell Science

100

130

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“…8,9 However, the exact mechanism remains elusive. Because neutrophils produce reactive oxygen species (ROS) within the leading edge during chemotaxis, 10,11 and the activity of the lipid phosphatase PTEN is markedly reduced by ROS, 12,13 we hypothesized that local ROS production in neutrophils could regulate PtdIns(3,4,5)P 3 levels through redox regulation of PTEN. We indeed identified PTEN to be a major target of chemoattractantinduced ROS formation and demonstrate that its enzymatic activity decreases accordingly.…”

Section: Introductionmentioning

confidence: 99%

Rac regulates PtdInsP3 signaling and the chemotactic compass through a redox-mediated feedback loop

Kuiper

Sun

Magalhães

et al. 2011

Blood

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IntroductionNeutrophils are important mediators of the innate immune system and are rapidly recruited from the circulation to sites of infection to eliminate pathogenic threats. Key to this recruitment is the release of chemoattractants by infected host tissue or pathogens, which subsequently form a chemical gradient that attracts neutrophils to the appropriate sites. 1 In response to a chemotactic gradient, neutrophils polarize and form a leading edge pointing toward the chemoattractant source and a posterior structure called the uropod. Actin polymerization within the leading edge drives up-gradient protrusion, whereas myosin activity in the uropod detaches the rear of the cell. The proper coordination of these polarized events is essential for directional migration and depends on the asymmetrical distribution of specific molecular determinants. A hallmark of neutrophil polarization is the asymmetrical accumulation of the phospholipid phosphatidylinositol(3,4,5)-trisphosphate [PtdIns(3,4,5)P 3 ] in the leading edge. 2,3 The formation of PtdIns(3,4,5)P 3 is catalyzed by PI3Ks and is counteracted by the activity of the lipid phosphatases phosphatase and tensin homolog (PTEN) and SH2-containing inositol phosphatase (SHIP), which generate the lipid products PtdIns(4,5)P 2 and PtdIns(3,4)P 2 , respectively. 4,5 Several studies have suggested that the establishment of a robust PtdIns(3,4,5)P 3 levels requires a positive feedback loop, and this is corroborated by the observation that the introduction of exogenous PtdIns(3,4,5)P 3 induces further accumulation of endogenous PtdIns(3,4,5)P 3 in a Rho GTPase-dependent fashion. 6,7 Rac and actin polymerization were both shown to be required for the establishment of PtdIns(3,4,5)P 3 polarization via a feedback loop mechanism. 8,9 However, the exact mechanism remains elusive. Because neutrophils produce reactive oxygen species (ROS) within the leading edge during chemotaxis, 10,11 and the activity of the lipid phosphatase PTEN is markedly reduced by ROS, 12,13 we hypothesized that local ROS production in neutrophils could regulate PtdIns(3,4,5)P 3 levels through redox regulation of PTEN. We indeed identified PTEN to be a major target of chemoattractantinduced ROS formation and demonstrate that its enzymatic activity decreases accordingly. Decreased PTEN activity led to an increase of PtdIns(3,4,5)P 3 , which could be reversed by ROS scavengers or genetic ablation of NADPH-oxidase 2 (NOX2). Consistent with this finding, reduction of ROS inhibited directional migration of neutrophils toward N-formyl-L-methionyl-L-leucyl-L-phenylalanine (fMLP), uncapping of actin filaments, and Rac activity. Although Rac GTPases are important downstream effectors of PtdIns(3,4,5)P 3 , they are also crucial for ROS production. Rescue experiments with small GTPase Rac effector mutants revealed that Rac facilitates PtdIns(3,4,5)P 3 accumulation and that this effect depends on its ability to activate NADPH-oxidase. Methods Abs and reagentsRabbit polyclonal Ab against phosphorylated AKT (Thr308; #2...

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“…Among the Rho GTPase subfamily, Rac2 is uniquely required for both fMLF-mediated chemotaxis and superoxide production of neutrophils (19,20,27,28). Studies using mutant mice have identified several Rac2 GEFs, including DOCK2 (29), GIT2 (30), and P-Rex1 (31), required for neutrophil function. Whereas DOCK2 and GIT2 regulate both Rac1 and Rac2 activities (29,30), genetic data suggest that P-Rex1 functions as a predominant Rac2 GEF in mouse neutrophils (31).…”

mentioning

confidence: 99%

“…Studies using mutant mice have identified several Rac2 GEFs, including DOCK2 (29), GIT2 (30), and P-Rex1 (31), required for neutrophil function. Whereas DOCK2 and GIT2 regulate both Rac1 and Rac2 activities (29,30), genetic data suggest that P-Rex1 functions as a predominant Rac2 GEF in mouse neutrophils (31). P-Rex1-deficient neutrophils demonstrate a selective defect in Rac2 activation following fMLF stimulation, and P-Rex1 2/2 neutrophils phenocopy many of the functional defects observed in Rac2 2/2 cells (19,27,31).…”

mentioning

confidence: 99%

The 3BP2 Adapter Protein Is Required for Chemoattractant-Mediated Neutrophil Activation

Chen

Dimitriou

Milne

et al. 2012

The Journal of Immunology

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3BP2 is a pleckstrin homology and Src homology 2 domain-containing adapter protein mutated in cherubism, a rare autosomal-dominant human bone disorder. Previously, we have demonstrated a functional role for 3BP2 in peripheral B cell development and in peritoneal B1 and splenic marginal zone B cell-mediated Ab responses. In this study, we show that 3BP2 is required for G protein-coupled receptor-mediated neutrophil functions. Neutrophils derived from 3BP2-deficient (Sh3bp2−/−) mice failed to polarize their actin cytoskeleton or migrate in response to a gradient of chemotactic peptide, fMLF. Sh3bp2−/− neutrophils failed to adhere, crawl, and emigrate out of the vasculature in response to fMLF superfusion. 3BP2 is required for optimal activation of Src family kinases, small GTPase Rac2, neutrophil superoxide anion production, and for Listeria monocytogenes bacterial clearance in vivo. The functional defects observed in Sh3bp2−/− neutrophils may partially be explained by the failure to fully activate Vav1 guanine nucleotide exchange factor and properly localize P-Rex1 guanine nucleotide exchange factor at the leading edge of migrating cells. Our results reveal an obligate requirement for the adapter protein 3BP2 in G protein-coupled receptor-mediated neutrophil function.

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Neutrophil direction sensing and superoxide production linked by the GTPase-activating protein GIT2

Cited by 73 publications

References 48 publications

Expanding functions of GIT Arf GTPase-activating proteins, PIX Rho guanine nucleotide exchange factors and GIT–PIX complexes

Expanding functions of GIT Arf GTPase-activating proteins, PIX Rho guanine nucleotide exchange factors and GIT–PIX complexes

Rac regulates PtdInsP3 signaling and the chemotactic compass through a redox-mediated feedback loop

The 3BP2 Adapter Protein Is Required for Chemoattractant-Mediated Neutrophil Activation

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