Myelin suppresses axon regeneration by PIR-B/SHP-mediated inhibition of Trk activity
Open Access
- 1 March 2011
- journal article
- research article
- Published by Springer Science and Business Media LLC in The EMBO Journal
- Vol. 30 (7), 1389-1401
- https://doi.org/10.1038/emboj.2011.55
Abstract
Paired immunoglobulin‐like receptor B (PIR‐B) partially mediates the regeneration‐inhibiting effects of the myelin‐derived protein Nogo, myelin‐associated glycoprotein (MAG), and oligodendrocyte‐myelin glycoprotein (OMgp). In this study, we report that inhibition of the PIR‐B signaling cascades in neurons enhances axon regeneration in the central nervous system (CNS). Binding of MAG to PIR‐B led to the association of PIR‐B with tropomyosin receptor kinase (Trk) neurotrophin receptors. Src homology 2‐containing protein tyrosine phosphatase (SHP)‐1 and SHP‐2, which were recruited to PIR‐B upon MAG binding, functioned as Trk tyrosine phosphatases. Further, SHP‐1 and SHP‐2 inhibition reduced MAG‐induced dephosphorylation of Trk receptors and abolished the inhibitory effect of MAG on neurite growth. Thus, PIR‐B associated with Trk to downregulate basal and neurotrophin‐regulated Trk activity through SHP‐1/2 in neurons. Moreover, in vivo transfection of small interfering RNA (siRNA) for SHP‐1 or SHP‐2 induced axonal regeneration after optic nerve injury in mice. Our results thus identify a new molecular target to enhance regeneration of the injured CNS.This publication has 48 references indexed in Scilit:
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