Fibrinogen inhibits neurite outgrowth via β3 integrin-mediated phosphorylation of the EGF receptor
Open accessAbstract
Changes in the molecular and cellular composition of the CNS after injury or disease result in the formation of an inhibitory environment that inhibits the regeneration of adult mammalian CNS neurons. Although a dramatic change in the CNS environment after traumatic injury or disease is hemorrhage because of vascular rupture or leakage of the blood-brain barrier, the potential role for blood proteins in repair processes remains unknown. Here we show that the blood protein fibrinogen is an inhibitor of neurite outgrowth that is massively deposited in the spinal cord after injury. We show that fibrinogen acts as a ligand for beta3 integrin and induces the transactivation of EGF receptor (EGFR) in neurons. Fibrinogen-mediated inhibition of neurite outgrowth is reversed by blocking either beta3 integrin or phoshorylation of EGFR. Inhibition of Src family kinases that mediate the cross-talk between integrin and growth factor receptors rescue the fibrinogen-induced phosphorylation of EGFR. These results identify fibrinogen as the first blood-derived inhibitor of neurite outgrowth and suggest fibrinogen-induced EGFR transactivation on neuronal cells as a molecular link between vascular and neuronal damage in the CNS after injury.
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Fibrinogen and its polymeric form fibrin can activate integrin receptors on glial cells and neurons to inhibit regeneration, or receptors on microglia and bone-derived macrophages to exacerbate neuroinflammation and induce antigen-presenting genes.
“For example, fibrinogen and its polymeric form fibrin can activate integrin receptors on glial cells and neurons to inhibit regeneration (45, 522), or receptors on microglia and bone-derived macrophages to exacerbate neuroinflammation and induce antigen-presenting genes (45, 132, 510).”
From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [522]
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RetractedAstrocytic tight junctions control inflammatory CNS lesion pathogenesis
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Patel, S., Govindarajan, V., Chakravarty, S., & Dubey, N. (2024) · International Immunopharmacology · doi:10.1016/j.intimp.2024.113326 · Cited by 10 · see citing works
- Authors
- Schachtrup, C., Lu, P., Jones, L. L., Lee, J. K., Lu, J., Sachs, B. D., Zheng, B., & Akassoglou, K.
- Affiliations
- Departments of *Pharmacology and
- University of California San Diego (US)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2007-07-10
- Volume
- 104
- Issue
- 28
- Pages
- 11814-11819
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC1913857
- OpenAlex
- W2083267292
- Cited by
- 117
- References
- 7
- Citations by year
- 2026: 2 · 2025: 5 · 2024: 9 · 2023: 5 · 2022: 5 · 2021: 2 · 2020: 8 · 2019: 8 · 2018: 8 · 2017: 5 · 2016: 6 · 2015: 10 · 2014: 3 · 2013: 4 · 2012: 6
- FWCI
- 2.39
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Christopher and Dana Reeve Foundation
- Multiple Sclerosis Society
- Deutsche Forschungsgemeinschaft
- National Institutes of Health (NS047101)
- National Institute of General Medical Sciences (T32GM007752)
- National Institute of Neurological Disorders and Stroke (R01NS054734, R01NS052189, P30NS047101, R01NS051470)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nerve injury and regeneration
- Health Sciences › Medicine › Immunology and Allergy › Cell Adhesion Molecules Research
- Health Sciences › Medicine › Neurology › Traumatic Brain Injury and Neurovascular Disturbances
- Keywords
- fibrinogen, neurite outgrowth inhibition, CD61, EGF receptor transactivation, EGFR phosphorylation, Src family kinases, spinal cord injury, central nervous system regeneration
- MeSH terms
- Animals, Female, Fibrinogen, Growth Inhibitors, Humans, Mice, Inbred C57BL, Neural Inhibition, Phosphorylation, Rats, Inbred F344, Transcriptional Activation, Neurites, Integrin beta3, Mice, Rats, ErbB Receptors
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