Retrograde TrkAIII transport from ERGIC to ER: a re-localisation mechanism for oncogenic activity
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Antonietta Rosella Farina1, Lucia Cappabianca1, Pierdomenico Ruggeri1,2, Luciana Gneo1, Rita Maccarone1 and Andrew Reay Mackay1
1 Department of Applied Clinical and Biotechnological Sciences, University of L’Aquila, L’Aquila, Italy
2 Department of Medical-Surgical Science and Biotechnology, University of Rome “La Sapienza”, Latina, Italy
Andrew Reay Mackay, email:
Keywords: TrkAIII oncoprotein, retrograde transport, activation mechanism, neuroblastoma, endoplasmic reticulum intermediate compartment
Received: July 31, 2015 Accepted: September 12, 2015 Published: September 22, 2015
In human SH-SY5Y neuroblastoma (NB) cells, nascent immature N-glycosylated 110kDa TrkA moves rapidly from the endoplasmic reticulum (ER) to the Golgi Network (GN), where it matures into the 140kDa receptor prior to being transported to the cell surface, creating GN and cell surface pools of inactive receptor maintained below the spontaneous activation threshold by a full compliment of inhibitory domains and endogenous PTPases. In contrast, the oncogenic alternative TrkAIII splice variant is not expressed at the cell surface but re-localises to intracellular membranes, within which it exhibits spontaneous ERGIC/COPI-associated activation and oncogenic Akt signalling. In this study, we characterise the mechanism responsible for TrkAIII re-localisation. Spontaneous TrkAIII activation, facilitated by D4 IG-like domain and N-glycosylation site omission, increases spontaneous activation potential by altering intracellular trafficking, inhibiting cell surface expression and eliminating an important inhibitory domain. TrkAIII, spontaneously activated within the permissive ERGIC/COPI compartment, rather than moving in an anterograde direction to the GN exhibits retrograde transport back to the ER, where it is inactivated. This sets-up self-perpetuating TrkAIII re-cycling between the ERGIC and ER, that ensures continual accumulation above the spontaneous activation threshold of the ERGIC/COPI compartment. This is reversed by TrkA tyrosine kinase inhibitors, which promote anterograde transport of inactivated TrkAIII to the GN, resulting in GN-associated TrkAIII maturation to a 120kDa species that is degraded at the proteasome.
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