The tropomyosin-relatedkinase (Trk) family of receptor tyrosine kinases controls synaptic function, plasticity and sustains differentiation, morphology,and neuronal cell survival. UnderstandingTrk receptors down-regulation and recycling is a crucial step to point out sympathetic and sensory neuron function and survival. PC12 cells derived from pheochromocytoma of the rat adrenal medulla have been widely used as a model system for studies of neuronal differentiation as they respond to nerve growth factor (NGF) with a dramatic change in phenotype and acquire a number of properties characteristic of sympathetic neurons. In this study we demonstrated that in PC12 cells theTrkA receptor interacts with the deubiquitinating enzyme USP8/UBPy in a NGF-dependent manner and that it is deubiquitinated in vivo and in vitro by USP8. USP8overexpressionblockedNGF-inducedneuritesoutgrowthwhilethe overexpressionofthecatalyticallyinactivemutantUSP8/UBPyC748A causedamarkedincreaseofcell differentiation.LocalizationandbiochemicalexperimentshavepointoutthatUSP8andTrkApartially co-localizeinendosomesafterNGFstimulation.FinallywehavestudiedtheroleplayedbyUSP8on TrkAturnover;usingspecific siRNAforUSP8wefoundthatUSP8knockdownincreasesTrkAhalf-life, suggestingthatthedeubiquitinatingactivityofUSP8promotesTrkAdegradation.
The deubiquitinating enzyme UBPy/USP8 interacts with TrkA and inhibits neuronal differentiation in PC12 cells / M. Ceriani, L. Amigoni, A. D'Aloia, G. Berruti, E. Martegani. - In: EXPERIMENTAL CELL RESEARCH. - ISSN 0014-4827. - 333:1(2015 Apr 10), pp. 49-59. [10.1016/j.yexcr.2015.01.019]
The deubiquitinating enzyme UBPy/USP8 interacts with TrkA and inhibits neuronal differentiation in PC12 cells
G. BerrutiPenultimo
;
2015
Abstract
The tropomyosin-relatedkinase (Trk) family of receptor tyrosine kinases controls synaptic function, plasticity and sustains differentiation, morphology,and neuronal cell survival. UnderstandingTrk receptors down-regulation and recycling is a crucial step to point out sympathetic and sensory neuron function and survival. PC12 cells derived from pheochromocytoma of the rat adrenal medulla have been widely used as a model system for studies of neuronal differentiation as they respond to nerve growth factor (NGF) with a dramatic change in phenotype and acquire a number of properties characteristic of sympathetic neurons. In this study we demonstrated that in PC12 cells theTrkA receptor interacts with the deubiquitinating enzyme USP8/UBPy in a NGF-dependent manner and that it is deubiquitinated in vivo and in vitro by USP8. USP8overexpressionblockedNGF-inducedneuritesoutgrowthwhilethe overexpressionofthecatalyticallyinactivemutantUSP8/UBPyC748A causedamarkedincreaseofcell differentiation.LocalizationandbiochemicalexperimentshavepointoutthatUSP8andTrkApartially co-localizeinendosomesafterNGFstimulation.FinallywehavestudiedtheroleplayedbyUSP8on TrkAturnover;usingspecific siRNAforUSP8wefoundthatUSP8knockdownincreasesTrkAhalf-life, suggestingthatthedeubiquitinatingactivityofUSP8promotesTrkAdegradation.
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