Vav Activation and Function as a Rac Guanine Nucleotide Exchange Factor in Macrophage Colony-Stimulating Factor-Induced Macrophage Chemotaxis
Open accessAbstract
Signal transduction mediated by phosphatidylinositol 3-kinase (PI 3-kinase) is regulated by hydrolysis of its products, a function performed by the 145-kDa SH2 domain-containing inositol phosphatase (SHIP). Here, we show that bone marrow macrophages of SHIP(-/-) animals have elevated levels of phosphatidylinositol 3,4,5-trisphosphate [PI (3,4,5)P(3)] and displayed higher and more prolonged chemotactic responses to macrophage colony-stimulating factor (M-CSF) and elevated levels of F-actin relative to wild-type macrophages. We also found that the small GTPase Rac was constitutively active and its upstream activator Vav was constitutively phosphorylated in SHIP(-/-) macrophages. Furthermore, we show that Vav in wild-type macrophages is recruited to the membrane in a PI 3-kinase-dependent manner through the Vav pleckstrin homology domain upon M-CSF stimulation. Dominant inhibitory mutants of both Rac and Vav blocked chemotaxis. We conclude that Vav acts as a PI 3-kinase-dependent activator for Rac activation in macrophages stimulated with M-CSF and that SHIP regulates macrophage M-CSF-triggered chemotaxis by hydrolysis of PI (3,4,5)P(3).
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MCSF signaling activates its receptor FMS tyrosine kinase, which sequentially activates PI-3 kinase and Rac in microglia and bone marrow derived cells.
“existing literature provides evidence that MCSF signaling activates its receptor the FMS tyrosine kinase which sequentially activates PI-3 kinase and Rac in microglia and bone marrow derived cells [48], [49].”
From Rac2 Controls Tumor Growth, Metastasis and M1-M2 Macrophage Differentiation In Vivo (2014) · cites this paper as [49]
The paper identifies c-fms as the M-CSF receptor and reports that M-CSF-induced Rac activation requires PI 3-kinase in bone marrow-derived macrophages (Abstract; “Macrophages lacking SHIP display elevated chemotactic responses,” page not provided). Its Animals section identifies the cells studied as bone marrow-derived macrophages; our copy does not establish the same signaling sequence in microglia. (LLM, conf=0.88)
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Cites
Liu, Q., Sasaki, T., Kozieradzki, I., Wakeham, A., Itie, A., Dumont, D. J., & Penninger, J. M. (1999) · Genes & Development · doi:10.1101/gad.13.7.786 · Cited by 341 · see citing works
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Rac2 Controls Tumor Growth, Metastasis and M1-M2 Macrophage Differentiation In Vivo
Joshi, S., Singh, A. R., Zulcic, M., Bao, L., Messer, K., Ideker, T., Dutkowski, J., & Durden, D. L. (2014) · PLoS ONE · doi:10.1371/journal.pone.0095893 · Cited by 128 · see citing works
Sindrilaru, A., Peters, T., Schymeinsky, J., Oreshkova, T., Wang, H., Gompf, A., Mannella, F., Wlaschek, M., Sunderkötter, C., Rudolph, K. L., et al. (2009) · Blood · doi:10.1182/blood-2008-07-166702 · Cited by 73 · see citing works
- Authors
- Vedham, V., Phee, H., & Coggeshall, K. M.
- Affiliations
- Oklahoma Medical Research Foundation (US)
- University of California, San Francisco (US)
- Corresponding author
- Coggeshall, K. Mark
- Venue
- Molecular and Cellular Biology
- Publisher
- Informa UK Limited
- Published
- 2005-05-01
- Volume
- 25
- Issue
- 10
- Pages
- 4211-4220
- ISSN
- 0270-7306 (ISSN-L)
- 1098-5549
- PMC
- PMC1087731
- OpenAlex
- W2134591087
- Cited by
- 76
- References
- 1
- Citations by year
- 2024: 1 · 2023: 1 · 2022: 2 · 2021: 1 · 2020: 2 · 2019: 2 · 2018: 6 · 2015: 4 · 2014: 4 · 2013: 7 · 2012: 6
- FWCI
- 2.64
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Molecular and Cellular Biology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Cancer Institute (R01CA064268, CA 64268)
- National Institute of Allergy and Infectious Diseases (AI 49264, R01AI049264)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
- Keywords
- Vav, Rac, guanine nucleotide exchange factor, macrophage colony-stimulating factor, macrophage chemotaxis, phosphatidylinositol 3,4,5-trisphosphate, phosphatidylinositol 3-kinase, signal transduction, pleckstrin homology domain, F-actin, bone marrow-derived macrophages
- MeSH terms
- Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases, Animals, Cell Membrane, Cells, Cultured, Chemotaxis, Enzyme Activation, Macrophages, Mice, Inbred C57BL, Phosphoric Monoester Hydrolases, Proto-Oncogene Proteins, Signal Transduction, Macrophage Colony-Stimulating Factor, Protein Structure, Tertiary, Phosphatidylinositol Phosphates, Cell Cycle Proteins, Phosphatidylinositol 3-Kinases, rac GTP-Binding Proteins, Protein Transport, Mice, Proto-Oncogene Proteins c-vav
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