Complement C5b-9 induces receptor tyrosine kinase transactivation in glomerular epithelial cells
A V Cybulsky1, T Takano, J Papillon
1Department of Medicine, McGill University Health Centre, Montreal, Quebec, Canada. cbulsky@pathology.lan.mcgill.ca
The American Journal of Pathology
|November 7, 1999
Summary
Complement component 5b-9 (C5b-9) triggers kidney injury in membranous nephropathy by activating receptor tyrosine kinases and the ERK2 cascade, leading to prostaglandin E2 production.
Area of Science:
- Nephrology
- Cell Biology
- Immunology
Background:
- Membranous nephropathy involves glomerular epithelial cell (GEC) injury and proteinuria.
- The complement component C5b-9 plays a role in GEC injury and proteinuria in the passive Heymann nephritis (PHN) model.
- Eicosanoids partially mediate C5b-9-induced GEC injury.
Purpose of the Study:
- Investigate the role of receptor tyrosine kinases (RTKs) in C5b-9-induced GEC injury.
- Elucidate the signaling pathways involved in C5b-9-mediated GEC activation.
- Determine the in vivo relevance of these pathways in the PHN model.
Main Methods:
- Utilized cultured rat GEC and isolated glomeruli from rats with PHN.
- Assessed tyrosine phosphorylation of RTKs and extracellular signal-regulated kinase-2 (ERK2).
- Measured arachidonic acid (AA) release and prostaglandin E2 (PGE2) production.
- Employed the EGF-R-selective tyrphostin AG1478 to inhibit specific pathways.
Main Results:
- Sublytic C5b-9 induced tyrosine phosphorylation of multiple RTKs (EGF-R, Neu, FGFR2, HGF-R) in cultured GEC.
- C5b-9 stimulated ERK2 phosphorylation, AA release, and PGE2 production.
- AG1478 partially blocked C5b-9-induced ERK2 phosphorylation, AA release, and PGE2 production (45-65%).
- PHN glomeruli showed increased ERK2 phosphorylation and PGE2 production, partially inhibited by AG1478.
Conclusions:
- C5b-9 induces transactivation of RTKs, leading to ERK2 activation, AA release, and PGE2 production in GEC.
- Activated tyrosine kinases may act as scaffolds for signaling complex assembly, activating the ERK2 cascade and AA metabolism.
- These findings highlight a novel mechanism of C5b-9-induced kidney injury involving RTK transactivation and eicosanoid production.
Related Concept Videos
01:00Enzyme-linked Receptors
Enzyme-linked receptors are proteins that act as both receptor and enzyme, activating multiple intracellular signals. This is a large group of receptors that include the receptor tyrosine kinase (RTK) family. Many growth factors and hormones bind to and activate the RTKs.
Neurotrophin (NT) receptors are a family of RTKs, including trkA, trkB, and trkC (tropomyosin-related kinase) receptors. TrkA is specific for nerve growth factor (NGF), neurotrophin-6, and neurotrophin-7. TrkB binds...
Neurotrophin (NT) receptors are a family of RTKs, including trkA, trkB, and trkC (tropomyosin-related kinase) receptors. TrkA is specific for nerve growth factor (NGF), neurotrophin-6, and neurotrophin-7. TrkB binds...
01:26Receptor Tyrosine Kinases
Receptor tyrosine kinases or RTKs are membrane-bound receptors that phosphorylate specific tyrosine on protein substrates. RTKs regulate cellular growth, differentiation, survival, and migration. They contain an extracellular ligand binding domain, a transmembrane domain, and a cytosolic tail with intrinsic kinase activity. Several extracellular signaling molecules activate RTKs in one or more ways and relay the signal downstream. Ligands such as platelet-derived growth factor (PDGF) or...
01:16TGF - β Signaling Pathway
The TGF-β signaling pathway regulates cell growth, differentiation, adhesion, motility, and development. TGF-β ligands that induce TGF-β signaling are synthesized in their latent form. Several proteases or cell surface receptors such as integrins act upon the latent form, releasing the active ligand. There are three types of mammalian TGF-βs: (TGF-β1, TGF-β2, and TGF-β3) that bind as homodimers or heterodimers to TGF-β receptors. The TGF-β receptors are of three kinds RI, RII, and RIII. The RI...
01:17Intracellular Signaling Affects Focal Adhesions
Integrins act both as extracellular input receivers and as intracellular processing activators. As their name suggests, integrins are entirely integrated into the membrane structure. Their hydrophobic membrane-spanning regions interact with the phospholipid bilayer's hydrophobic region. These membrane receptors provide extracellular attachment sites for effectors like hormones and growth factors. They activate intracellular response cascades when their effectors are bound and active.
Some...
Some...
01:27Transducer Mechanism: Enzyme-Linked Receptors
Enzyme-linked receptors are cell-surface receptors acting as an enzyme or associating with an enzyme intracellularly. They make excellent drug targets. Drugs can bind to the extracellular ligand-binding domain or directly affect their enzymatic domain and alter their activity.
Major types that are helpful drug targets include:
Major types that are helpful drug targets include:
01:27Complement System
The complement system is a group of approximately 20 plasma proteins that strengthen the body's defenses against infections through opsonization, inflammation, and cell lysis. Opsonization involves coating pathogens with complement proteins, making them more recognizable and facilitating phagocyte engulfment. Certain complement proteins induce inflammation that attracts immune cells to the site of infection. Cell lysis involves the destruction of pathogens through the formation of a membrane...