Fig. 4

TrkAIII recycles between the ERGIC and ER compartments. Schematic representation of: a) fully spliced TrkA receptor trafficking from intracellular to cell surface compartments, characterised by anterograde transport of inactive immature TrkA receptors from the ER to the ERGIC and GN, where they are matured prior to being transported to the cell surface plus the fate of neurotrophin-activated cell surface TrkA receptors that exhibit motor protein-dependent MT minus-end directed retrograde transport to the GN, associated with the activation of tumour suppressing Ras/MAPK signaling. b) TrkAIII intracellular trafficking, characterised by anterograde transport of inactive immature TrkAIII from the ER to the ERGIC, spontaneous activation within ERGOC/COPI membranes that blocks anterograde transport to the GN and promotes MT minus-end directed retrograde transport of active TrkAIII back to the ER and centrosome, setting up self perpetual TrkAIII recycling between the ER and ERGIC, partial UPR activation, PIP3K/Akt/NF-κB pro-survival and pro-angiogenic signaling, centrosome amplification, chromosome instability, formation of micronuclei and increased MTOC activity. c) Altered TrkAIII trafficking in the presence of Trk tyrosine kinase inhibitor, characterised by the uninhibited anterograde transport of inactive TrkAIII from the ER to ERGIC and GN, resulting in GN-associated gp120kDa TrkAIII maturation, degradation of mature TrkAIII at the proteasome and the inhibition of TrkAIII oncogenic activity