Limits...
Receptor tyrosine kinases: molecular switches regulating CNS axon regeneration.

Vigneswara V, Kundi S, Ahmed Z - J Signal Transduct (2012)

Bottom Line: The insufficient or lack of trophic support for injured neurons is considered as one of the major obstacles contributing to their failure to survive and regrow their axons after injury.In the CNS, many of the signalling pathways associated with neuronal survival and axon regeneration are regulated by several classes of receptor tyrosine kinases (RTK) that respond to a variety of ligands.This paper highlights and summarises the most relevant recent findings pertinent to different classes of the RTK family of molecules, with a particular focus on elucidating their role in CNS axon regeneration.

View Article: PubMed Central - PubMed

Affiliation: Neuropharmacology and Neurobiology Section, School of Clinical and Experimental Medicine, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK.

ABSTRACT
The poor or lack of injured adult central nervous system (CNS) axon regeneration results in devastating consequences and poor functional recovery. The interplay between the intrinsic and extrinsic factors contributes to robust inhibition of axon regeneration of injured CNS neurons. The insufficient or lack of trophic support for injured neurons is considered as one of the major obstacles contributing to their failure to survive and regrow their axons after injury. In the CNS, many of the signalling pathways associated with neuronal survival and axon regeneration are regulated by several classes of receptor tyrosine kinases (RTK) that respond to a variety of ligands. This paper highlights and summarises the most relevant recent findings pertinent to different classes of the RTK family of molecules, with a particular focus on elucidating their role in CNS axon regeneration.

No MeSH data available.


Related in: MedlinePlus

Molecular pathway of PIR-B signal transduction. Binding of appropriate ligands to PirB leads to formation of a receptor complex along with TrkB which then recruits SHP1/2 and their interaction deactivated TrkB and therefore neurite outgrowth is inhibited. Adapted from [108].
© Copyright Policy - open-access
Related In: Results  -  Collection


getmorefigures.php?uid=PMC3405719&req=5

fig4: Molecular pathway of PIR-B signal transduction. Binding of appropriate ligands to PirB leads to formation of a receptor complex along with TrkB which then recruits SHP1/2 and their interaction deactivated TrkB and therefore neurite outgrowth is inhibited. Adapted from [108].

Mentions: The importance of paired immunoglobulin-like receptor B (PIR-B)-mediated inhibition of TrkB activity and its role in axon regeneration has recently been reported. PIR-B is considered as a high affinity receptor for myelin-derived axon growth inhibitory ligands such as Nogo, MAG, and OMgp [93] and inhibition of PIR-B-mediated signalling pathways enhanced axon regeneration of axotomized RGC in vivo [94]. This study further postulated that a state of imbalance between the expression of TrkB and PIR-B modulate the sustainable axon regeneration of injured axons. Upon downregulation of TrkB, ligands such as BDNF and NT-4/5 and the inhibitory molecules in the CNS that bind to PIR-B form a receptor complex with TrkB and the consequent recruitment of Src homology 2-containing protein tyrosine phosphatase (SHP-1/2). This in turn induces dephosphorylation of the kinase catalytic domain of TrkB and blocks axon regeneration (Figure 4). In the presence of an axon growth inhibitory environment, agents that either activate TrkB or inhibit the binding of BDNF to p75NTR can be used as better therapeutic candidates in CNS axon regeneration since the BDNF/  p75NTR complex potentially compromises the ability of BDNF to activate TrkB to enhance growth of axotomized CNS axons [95]. On the basis of these studies and despite the extensive use of neurotrophins, the family of Trk receptors raises challenging issues in terms of signalling cascades and their regulatory mechanisms in axon regeneration in the CNS. There are many issues, which remain to be explored, and obstacles to be tackled in the in vivo uses of neurotrophins as therapeutics in the treatment of CNS injuries. These issues will be briefly discussed later in this paper.


Receptor tyrosine kinases: molecular switches regulating CNS axon regeneration.

Vigneswara V, Kundi S, Ahmed Z - J Signal Transduct (2012)

Molecular pathway of PIR-B signal transduction. Binding of appropriate ligands to PirB leads to formation of a receptor complex along with TrkB which then recruits SHP1/2 and their interaction deactivated TrkB and therefore neurite outgrowth is inhibited. Adapted from [108].
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3405719&req=5

fig4: Molecular pathway of PIR-B signal transduction. Binding of appropriate ligands to PirB leads to formation of a receptor complex along with TrkB which then recruits SHP1/2 and their interaction deactivated TrkB and therefore neurite outgrowth is inhibited. Adapted from [108].
Mentions: The importance of paired immunoglobulin-like receptor B (PIR-B)-mediated inhibition of TrkB activity and its role in axon regeneration has recently been reported. PIR-B is considered as a high affinity receptor for myelin-derived axon growth inhibitory ligands such as Nogo, MAG, and OMgp [93] and inhibition of PIR-B-mediated signalling pathways enhanced axon regeneration of axotomized RGC in vivo [94]. This study further postulated that a state of imbalance between the expression of TrkB and PIR-B modulate the sustainable axon regeneration of injured axons. Upon downregulation of TrkB, ligands such as BDNF and NT-4/5 and the inhibitory molecules in the CNS that bind to PIR-B form a receptor complex with TrkB and the consequent recruitment of Src homology 2-containing protein tyrosine phosphatase (SHP-1/2). This in turn induces dephosphorylation of the kinase catalytic domain of TrkB and blocks axon regeneration (Figure 4). In the presence of an axon growth inhibitory environment, agents that either activate TrkB or inhibit the binding of BDNF to p75NTR can be used as better therapeutic candidates in CNS axon regeneration since the BDNF/  p75NTR complex potentially compromises the ability of BDNF to activate TrkB to enhance growth of axotomized CNS axons [95]. On the basis of these studies and despite the extensive use of neurotrophins, the family of Trk receptors raises challenging issues in terms of signalling cascades and their regulatory mechanisms in axon regeneration in the CNS. There are many issues, which remain to be explored, and obstacles to be tackled in the in vivo uses of neurotrophins as therapeutics in the treatment of CNS injuries. These issues will be briefly discussed later in this paper.

Bottom Line: The insufficient or lack of trophic support for injured neurons is considered as one of the major obstacles contributing to their failure to survive and regrow their axons after injury.In the CNS, many of the signalling pathways associated with neuronal survival and axon regeneration are regulated by several classes of receptor tyrosine kinases (RTK) that respond to a variety of ligands.This paper highlights and summarises the most relevant recent findings pertinent to different classes of the RTK family of molecules, with a particular focus on elucidating their role in CNS axon regeneration.

View Article: PubMed Central - PubMed

Affiliation: Neuropharmacology and Neurobiology Section, School of Clinical and Experimental Medicine, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK.

ABSTRACT
The poor or lack of injured adult central nervous system (CNS) axon regeneration results in devastating consequences and poor functional recovery. The interplay between the intrinsic and extrinsic factors contributes to robust inhibition of axon regeneration of injured CNS neurons. The insufficient or lack of trophic support for injured neurons is considered as one of the major obstacles contributing to their failure to survive and regrow their axons after injury. In the CNS, many of the signalling pathways associated with neuronal survival and axon regeneration are regulated by several classes of receptor tyrosine kinases (RTK) that respond to a variety of ligands. This paper highlights and summarises the most relevant recent findings pertinent to different classes of the RTK family of molecules, with a particular focus on elucidating their role in CNS axon regeneration.

No MeSH data available.


Related in: MedlinePlus