The location of neurotrophin stimulation appears to determine the nature of the transcriptional response through differential uses of individual MAP kinases. The ERK5 pathway has a unique function in retrograde signalling; in contrast, ERK1/2, which mediate nuclear responses following direct cell body stimulation, does not transmit a retrograde signal. Following neurotrophin stimulation of distal axons, phosphorylated TRK receptors are endocytosed and transported to the cell bodies, where MEK5 phosphorylates ERK5, leading to ERK5 nuclear translocation, phosphorylation of transcription factors, and neuronal survival. In contrast, neurotrophin stimulation of the cell bodies causes concurrent activation and nuclear transport of ERK1/2 as well as ERK5. Several distinctive features of the ERK5 pathway might be important for retrograde signalling. The ERK5 cascade does not depend on activation of the G-protein RAS. Instead, this pathway may use other G-proteins such as RAP that are associated with vesicles, or may not require any G-protein intermediate. Another distinctive feature is that the MEK5 isoform, which is expressed in the nervous system, exhibits a punctate staining pattern, suggesting a vesicular localization. ERK5 itself significantly differs from ERK1/2, and its substrate specificity also differs from ERK1/2. For instance, ERK5 directly activates transcription factors, including MEF2, that are not phosphorylated by ERK1/2. Conversely, ERK1/2, but not ERK5, activate transcription factors such as ELK1 and MITF.