Receptor tyrosine kinases: molecular switches regulating CNS axon regeneration

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.

Figure 1

Different classes of RTK. RTK share tyrosine kinase domains in the intracellular portion while the extracellular portion contains cysteine repeat regions and single cysteine residues (circles). RTK family has a variety of ligands and receptors.

Figure 2

Activation of RTK signal transduction. (a) Inactive RTK are monomeric but after ligand binding dimerization of the extracellular domain occurs (b) and since cytoplasmic domains are juxtaposed, phosphorylation of tyrosine residues (ovals with Tyr labels) is facilitated. Phosphorylation allows inactive proteins to interact with the tyrosine residues and elicit appropriate cellular responses. Adapted from [50] Hubbard, 2004.

Figure 3

Schematic diagram summarizing the known possible TrkB signalling pathways associated with neuronal plasticity. Within neurons (dotted square), BDNF can induce three types of Trk B dimers to form: (1) TK+ homodimer; (2) TK ± T1 heterodimer and (3) T1 homodimer. The TK+ homodimer results in activation of PLCγ and PKC, which promote synaptic plasticity. Shc proteins activate the PI3K-Akt pathway and cell survival while Ras-MAPK pathway activation regulates differentiation. The function of the TK ± T1 heterodimer remains unknown. The T1 homodimer is important in synaptic transmission within neurons but a mechanism for this phenomena has not yet been elucidated. However, T1 is the major isoform of TrkB receptors in astrocytes (grey box), which induces release of Rho GDI1 and is involved in a Ca²⁺ influx in astrocytes. A TTIP (truncated TrkB-interacting protein) binds T1 but its functions are not yet clear. Adapted from [69].

Figure 4

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].