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Cited by 25Protein Kinase Regulation and GTPase SignalingCell Adhesion Molecules ResearchAngiogenesis and VEGF in Cancer

Expression of RAC2 in endothelial cells is required for the postnatal neovascular response

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De, Pradip, Peng, Qiong, Traktuevc, Dmitry O., Li, Weiming, Yoder, Mervin C., March, Keith L., Durden, Donald L.·2009·Experimental Cell Research
DOI 10.1016/j.yexcr.2008.10.003PMC PMC2767303
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Abstract

Herein, we describe an obligate role for the hematopoietic specific GTPase, RAC2 in endothelial integrin signaling and the postnatal neovascularization response in vivo. Using a Rac2 knockout mouse model, we discovered that despite the presence of both RAC1 and RAC2 protein in endothelial cells, RAC2 is obligately required for the postnatal neovascular response and alphavbeta3/ alpha4beta1/alpha5beta1 integrin-directed migration on vitronectin, H296 and CH271, fibronectin fragments, respectively. The molecular basis for RAC2 specificity was explored. A genetic analysis of Syk -/+ or Syk-/+;Rac2 -/+ mice revealed that SYK kinase is required for the integrin induced activation of RAC2. The analysis of endothelial cells from Rac2-/+ versus Syk-/+;Rac2-/+ mice provided genetic evidence that SYK-RAC2 signaling axis regulates integrin (alphavbeta3, alpha4beta1 and alpha5beta1) dependent migration. Our results provide evidence that a specific region of the nonreceptor protein tyrosine kinase, SYK, the B linker region containing Y342 and Y346 is required for SYK's regulation of RAC2 and integrin dependent migration. Moreover, the capacity of mice to vascularize the ischemic hindlimb following femoral artery ligation or matrigel plugs was markedly reduced in mice homozygous deficient for the Rac2 gene. These findings identify a novel signaling axis for the induction and potential modulation of postnatal angiogenesis.

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  • Rac2 knockout mice display a number of hematopoietic defects mostly in blood cell-specific receptor function or hematopoietic-specific effector mechanisms and in kinase pathway-activated cell survival.

    “the Rac2 knockout mice display a number of hematopoietic defects mostly in the context of blood cell-specific receptor function or hematopoietic-specific effector mechanisms and also in kinase pathway-activated cell survival [1], [2], [6], [7], [8].”

    From Rac2 Controls Tumor Growth, Metastasis and M1-M2 Macrophage Differentiation In Vivo (2014) · cites this paper as [1]

    The Introduction (page unavailable) reports neutrophil, macrophage, and mast-cell defects in Rac2 knockout mice. The Results discuss integrin-directed signaling and SYK-dependent RAC2 activation, but in endothelial cells; the cited paper does not establish kinase pathway-activated cell-survival defects in the knockout mice. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • In the absence of Rac2, macrophages and/or neutrophils display defective chemotaxis.

    “Previous findings clearly demonstrate that in the absence of Rac2, macrophages and/or neutrophils display suppressed reactive oxygen species (ROS) production, defective chemotaxis, impaired phagocytosis, and decreased microbial killing [1], [2], [6], [7], [8].”

    From Rac2 Controls Tumor Growth, Metastasis and M1-M2 Macrophage Differentiation In Vivo (2014) · cites this paper as [1]

    The Results section states that previous work found RAC2 necessary for macrophage integrin-directed migration. That supports a related migration defect, but integrin-directed migration is not the same as chemotaxis, and this paper does not report defective chemotaxis in RAC2-deficient macrophages or neutrophils. No page number is available in our copy. (LLM, conf=0.82)

    Experimental — accuracy not yet measured

  • α4β1/αvβ3-induced migration requires Rac2 in macrophages and endothelial cells, and this pathway regulates the postnatal angiogenic response in vivo.

    “The current investigation began with our initial observation that the provisional integrins, α4β1/αvβ3 induced migration requires a specific isoform of Rac, Rac2 in macrophages and endothelial cells and that this pathway regulated the postnatal angiogenic response in vivo [1], [2].”

    From Rac2 Controls Tumor Growth, Metastasis and M1-M2 Macrophage Differentiation In Vivo (2014) · cites this paper as [1]

  • In the absence of Rac2, macrophages and/or neutrophils display decreased microbial killing.

    “Previous findings clearly demonstrate that in the absence of Rac2, macrophages and/or neutrophils display suppressed reactive oxygen species (ROS) production, defective chemotaxis, impaired phagocytosis, and decreased microbial killing [1], [2], [6], [7], [8].”

    From Rac2 Controls Tumor Growth, Metastasis and M1-M2 Macrophage Differentiation In Vivo (2014) · cites this paper as [1]

    The Results section discusses RAC2-dependent macrophage migration, while the References list a study of neutrophil function and host defense. Neither passage states that Rac2-deficient macrophages or neutrophils have decreased microbial killing. Searches for microbial killing, killing, and infection found no passage addressing that outcome. (LLM, conf=0.72)

    Experimental — accuracy not yet measured

  • In the absence of Rac2, macrophages and/or neutrophils display suppressed reactive oxygen species (ROS) production.

    “Previous findings clearly demonstrate that in the absence of Rac2, macrophages and/or neutrophils display suppressed reactive oxygen species (ROS) production, defective chemotaxis, impaired phagocytosis, and decreased microbial killing [1], [2], [6], [7], [8].”

    From Rac2 Controls Tumor Growth, Metastasis and M1-M2 Macrophage Differentiation In Vivo (2014) · cites this paper as [1]

    The Results discuss RAC2-dependent macrophage migration, while the paper’s experiments concern endothelial migration and neovascularization. A References entry names a study of RAC2 and neutrophil NADPH oxidase activation, but no passage in our copy reports suppressed ROS production in RAC2-deficient macrophages or neutrophils (searched: ROS, reactive oxygen species, oxidative burst, and NADPH oxidase). (LLM, conf=0.72)

    Experimental — accuracy not yet measured

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Cited by

Sorted by citations

Authors
De, P., Peng, Q., Traktuevc, D. O., Li, W., Yoder, M. C., March, K. L., & Durden, D. L.
Affiliations
  • Emory University (US)
  • Indiana University Indianapolis (US)
Corresponding author
Durden, Donald L.
ORCID
Venue
Experimental Cell Research
Publisher
Elsevier BV
Published
2009-01
Volume
315
Issue
2
Pages
248-263
ISSN
0014-4827 (ISSN-L)
DOI
10.1016/j.yexcr.2008.10.003
PMC
PMC2767303
OpenAlex
W1965784559
Cited by
25
References
1
Citations by year
2025: 1 · 2023: 2 · 2022: 3 · 2021: 1 · 2020: 2 · 2019: 3 · 2018: 1 · 2017: 1 · 2016: 1 · 2015: 2 · 2014: 3 · 2013: 4
FWCI
0.14
Type
journal article
Language
en
Update notices
erratum (2009-10-01)
Open access
Licence
Locations
  • Experimental Cell Research (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • IUScholarWorks (Indiana University) (submittedVersion)
Funders
  • Georgia Cancer Coalition
  • Emory University
  • National Institutes of Health (R56CA94233)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
  • Health Sciences › Medicine › Immunology and Allergy › Cell Adhesion Molecules Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
Keywords
Rac2, endothelial cells, angiogenesis, integrin signaling, Syk, Rac1, integrin αvβ3, alpha4beta1 integrin, alpha5beta1 integrin, cell migration, vitronectin, fibronectin fragments, hindlimb ischemia
MeSH terms
Syk Kinase, RAC2 GTP-Binding Protein, Animals, Cell Movement, Chlorocebus aethiops, Fibronectins, Hindlimb, Humans, Mice, Inbred C57BL, Neuropeptides, Papio, Protein-Tyrosine Kinases, Regional Blood Flow, Signal Transduction, Reperfusion Injury, Gene Expression, Mice, Knockout, Neovascularization, Physiologic, Vitronectin, COS Cells, rac GTP-Binding Proteins, rac1 GTP-Binding Protein, RNA, Small Interfering, Integrin alpha4beta1, Integrin alphaVbeta3, Endothelial Cells, Intracellular Signaling Peptides and Proteins, Mice

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