††††††††††† Neurotrophins promote an exceptionally varied set of responses that require highly regulated signal transduction mechanisms.† Many factors can contribute to the complexity of the cellular responses elicited by neurotrophins through the Trk receptors, including the types of Trk receptor, neurotrophin ligand and signalling molecules involved, as well as the location and timing of the response.†
The set of Trk receptors expressed by a neuron determines the set of neurotrophins able to promote that neuronís survival and differentiation, and the possible downstream signalling pathways that can be elicited.† For example, the survival of sympathetic neurons requires the continuous activation of TrkA receptors.† Whether the Trk receptor is full-length or truncated also has an effect.† It has been shown that truncated TrkB isoforms that lack the kinase domain are associated with aggressive neuroblastomas and a poor prognosis, possibly by their ability to scavenge BDNF and remove it from circulation.† In contrast, the high expression of full-length TrkA in neuroblastomas correlates with increased patient survival.
Different neurotrophin ligands can elicit different responses from the same Trk receptor.† For example, TrkB can activate different signalling pathways in response to BDNF or NT4 binding.† In addition, pro-neurotrophins can elicit a different response from mature forms, as well as activating different receptors.† As a result, the extent of neurotrophin processing can alter neuronal outcome, where a higher level of processing favours Trk-mediated survival, and less processing favours p75NTR-mediated cell death.
The timing of the Trk-mediated stimulation can also affect the outcome of the response, where variations in Trk stimulation can affect the amplitude of the response, which in turn can result in the induction of distinct downstream signalling pathways that elicit different biological outcomes.† For example, sustained Ras activation (possibly through TrkA stimulation) can promote differentiation, while transient Ras activation (possibly through TrkB stimulation) can result in proliferation.†
Different neuronal cell types can express different Trk receptors leading to cell-type specific responses.† Proprioceptive neurons express TrkC and respond to NT3, which induces Akt stimulation that is critical for branching and for increasing axonal calibre.† In contrast, nociceptive sensory neurons express TrkA and respond to NGF, which favours Raf stimulation that is responsible for axonal elongation.† Also, the localisation of Trk receptors on axons of presynaptic cells can have a different response from their localisation on dendrites of postsynaptic cells or on the plasma membrane of the cell soma.† Internalisation of receptor/signalling complexes can modify a response, often by increasing MAPK activation or reducing PI3K activation.