The small GTPase Rap1b negatively regulates neutrophil chemotaxis and transcellular diapedesis by inhibiting Akt activation

Kumar, Sachin; Xu, Juying; Kumar, Ravi; Lakshmikanthan, Sribalaji; Kapur, Reuben; Kofron, Matthew; Chrzanowska‐Wodnicka, Magdalena; Filippi, Marie–Dominique

doi:10.1083/jcb.2064oia142

Cited by 6 publications

(9 citation statements)

References 56 publications

(96 reference statements)

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“…This study identifies Rap1b, which acts downstream of Axin2 and is essential for skeletal development. Although Rap1b has been implicated in angiogenesis, lens epithelial maintenance, and immune cell functions, (21,22,(49)(50)(51)(52)(53) its role in skeletogenesis has yet to be reported. In humans, multiple omics studies have recently identified Rap1b as one of the genes associated with bone mineral density and male osteoporosis.…”

Section: Discussionmentioning

confidence: 99%

Rap1b Is an Effector of Axin2 Regulating Crosstalk of Signaling Pathways During Skeletal Development

Maruyama

Jiang

Abbott

et al. 2017

Journal of Bone and Mineral Research

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Recent identification and isolation of suture stem cells capable of long term self-renewal, clonal expanding and differentiating demonstrate their essential role in calvarial bone development, homeostasis and injury repair. These bona fide stem cells express high level of Axin2 and are able to mediate bone regeneration and repair in a cell autonomous fashion. The importance of Axin2 is further demonstrated by its genetic inactivation in mice causing skeletal deformities resembling craniosynostosis in humans. The fate determination and subsequent differentiation of Axin2+ stem cells are highly orchestrated by a variety of evolutionary conserved signaling pathways including Wnt, FGF and BMP. These signals are often antagonistic of each other and possess differential effects on osteogenic and chondrogenic cell types. However, the mechanisms underlying the interplay of these signaling transductions remain largely elusive. Here we identify Rap1b acting downstream of Axin2 as a signaling interrogator for FGF and BMP. Genetic analysis reveals that Rap1b is essential for development of craniofacial and body skeletons. Axin2 regulates Rap1b through modulation of canonical BMP signaling. The BMP-mediated activation of Rap1b promotes chondrogenic fate and chondrogenesis. Furthermore, by inhibiting MAPK signaling, Rap1b mediates the antagonizing effect of BMP on FGF to repress osteoblast differentiation. Disruption of Rap1b in mice not only enhances osteoblast differentiation but also impairs chondrocyte differentiation during intramembranous and endochondral ossifications, respectively, leading to severe defects in craniofacial and body skeletons. Our findings reveal a dual role of Rap1b in development of the skeletogenic cell types. Rap1b is critical for balancing the signaling effects of BMP and FGF during skeletal development and disease.

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Section: Discussionmentioning

confidence: 99%

Rap1b Is an Effector of Axin2 Regulating Crosstalk of Signaling Pathways During Skeletal Development

Maruyama

Jiang

Abbott

et al. 2017

Journal of Bone and Mineral Research

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“…For example, following chemokine stimulation of neutrophils, dissociation of Shp1 from the membrane, which is associated with reduced phosphorylation of Pirb, temporarily releases a brake on signaling to maximize downstream MAPK signaling [32]. Relocalization of Shp1 to the uropod may also affect the migratory capacity of chemokinestimulated neutrophils [33]. How all of these overlapping features of Shp1 regulation work together to coordinate phosphatase function is not fully understood.…”

Section: Shp1 Structure and Regulationmentioning

confidence: 99%

“…Rap1b has been implicated through studies of neutrophils deficient in this enzyme. Kumar et al [33] found that neutrophils lacking Rap1b show enhanced migration and chemotaxis and reduced integrindependent superoxide production in vitro and enhanced recruitment to the lung in response to LPS challenge in vivo. Rap1b is thought to activate Shp1, although the mechanism is not known, suggesting a potential feedback loop to regulate integrin adhesion.…”

Section: Neutrophilsmentioning

confidence: 99%

Shp1 function in myeloid cells

Abram

Lowell

2017

Journal of Leukocyte Biology

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The mouse was first described in 1975 as a model of systemic inflammation and autoimmunity, as a result of immune system dysregulation. The phenotype was later ascribed to mutations in the cytoplasmic tyrosine phosphatase Shp1. This phosphatase is expressed widely throughout the hematopoietic system and has been shown to impact a multitude of cell signaling pathways. The determination of which cell types contribute to the different aspects of the phenotype caused by global Shp1 loss or mutation and which pathways within these cell types are regulated by Shp1 is important to further our understanding of immune system regulation. In this review, we focus on the role of Shp1 in myeloid cells and how its dysregulation affects immune function, which can impact human disease.

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“…In the present study, CLLV-1 significantly abrogated the Akt activation in response to various stimuli in human neutrophils (Fig 3 and EV2) and the CLLV-1-targeted Cys310 of Akt was identical among Akt1/2/3 ( Fig 6), suggesting that CLLV-1 covalently react with both Akt1 and Akt2 in neutrophils. It has been reported that Akt controls p47 phox phosphorylation and F-actin polymerization to trigger respiratory burst and chemotaxis in neutrophils, respectively (Chen et al, 2010;El-Benna et al, 2009;Kumar et al, 2014). CLLV-1 dose-dependently restricted the Akt-mediated p47 phox phosphorylation and F-actin levels in fMLF-activated human neutrophils and dHL-60 cells (Fig 1, 2 and 4), confirming that CLLV-1-inhibited Akt activity is critical for following inflammatory activation in human neutrophils.…”

Section: Discussionmentioning

confidence: 99%

“…Pharmacological inhibition of phospho-phosphoinositide 3-kinase (PI3K)/Akt signaling reduces the leukocyte degranulation (Hoenderdos et al, 2016;Nanamori et al, 2007). Akt also stabilizes F-actin polymerization to enhance the chemotaxis of activated neutrophils (Chen et al, 2010;Chodniewicz & Zhelev, 2003;Kumar et al, 2014). Therefore, Akt may be a potential pharmacological target to treat neutrophilic inflammation.…”

Section: Introductionmentioning

confidence: 99%

Targeting redox regulatory site of protein kinase B impedes neutrophilic inflammation in lung injury

Chen

Lee

et al. 2018

Preprint

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Neutrophil activation has a pathogenic effect in inflammatory diseases. Protein kinase B (PKB)/Akt regulates diverse cellular responses. However, the significance of Akt in neutrophilic inflammation is still not well understood. Here, we identified 5,7-dimethoxy-1,4-phenanthrenequinone (CLLV-1) as a novel Akt inhibitor. CLLV-1 inhibited respiratory burst, degranulation, and chemotaxis in activated human neutrophils and neutrophil-like differentiated HL-60 (dHL-60) cells. CLLV-1 selectively inhibited Akt phosphorylation in activated human neutrophils and dHL-60 cells.

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The small GTPase Rap1b negatively regulates neutrophil chemotaxis and transcellular diapedesis by inhibiting Akt activation

Cited by 6 publications

References 56 publications

Rap1b Is an Effector of Axin2 Regulating Crosstalk of Signaling Pathways During Skeletal Development

Rap1b Is an Effector of Axin2 Regulating Crosstalk of Signaling Pathways During Skeletal Development

Shp1 function in myeloid cells

Targeting redox regulatory site of protein kinase B impedes neutrophilic inflammation in lung injury

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