Journal
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH
Volume 1813, Issue 8, Pages 1428-1437Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/j.bbamcr.2011.04.006
Keywords
Receptor tyrosine kinase; Insulin-like growth factor receptor type 1; Regenerative medicine; Gene therapy; Oligodendrocyte progenitor; Chimeric receptor
Categories
Funding
- National Multiple Sclerosis Society of the USA
- Arthritis Research Campaign, UK
- Advisory Board of Barts and The London, UK
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In order to generate neural stem cells with increased ability to survive after transplantation in brain parenchyma we developed a chimeric receptor (ChR) that binds to myelin oligodendrocyte glycoprotein (MOG) via its ectodomain and activates the insulin-like growth factor receptor type 1 (IGF1R) signalling cascade. Activation of this pro-survival pathway in response to ligand broadly available in the brain might increase neuroregenerative potential of transplanted precursors. The ChR was produced by fusing a MOG-specific single chain antibody with the extracellular boundary of the IGF1R transmembrane segment. The ChR is expressed on the cellular surface, predominantly as a monomer, and is not N-glycosylated. To show MOG-dependent functionality of the ChR, neuroblastoma cells B104 expressing this ChR were stimulated with monolayers of cells expressing recombinant MOG. The ChR undergoes MOG-dependent tyrosine phosphorylation and homodimerisation. It promotes insulin and IGF-independent growth of the oligodendrocyte progenitor cell line CG4. The proposed mode of the ChR activation is by MUG-induced dimerisation which promotes kinase domain transphosphorylation, by-passing the requirement of conformation changes known to be important for IGF1R activation. Another ChR, which contains a segment of the p-chain ectodomain, was produced in an attempt to recapitulate some of these conformational changes, but proved non-functional. (C) 2011 Elsevier B.V. All rights reserved.
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