Fibrinogen inhibits neurite outgrowth via beta 3 integrin-mediated phosphorylation of the EGF receptor.
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.
Schachtrup
Christian
C
Department of Pharmacology, University of California at San Diego, La Jolla, CA 92093, USA.
Lu
Paul
P
Jones
Leonard L
LL
Lee
Jae K
JK
Lu
Jerry
J
Sachs
Ben D
BD
Zheng
Binhai
B
Akassoglou
Katerina
K
D000818:Animals; D066246:ErbB Receptors / Q000378:metabolism* / Q000502:physiology; D005260:Female; D005340:Fibrinogen / Q000378:metabolism / Q000502:physiology*; D006131:Growth Inhibitors / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D039661:Integrin beta3 / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009433:Neural Inhibition / Q000502:physiology*; D016501:Neurites / Q000378:metabolism* / Q000502:physiology; D010766:Phosphorylation; D051381:Rats; D011916:Rats, Inbred F344; D015533:Transcriptional Activation / Q000502:physiology
D006131:Growth Inhibitors; D039661:Integrin beta3; D005340:Fibrinogen; D066246:ErbB Receptors