intriguingly , mtorc1 activity only regulates the expression of nedd41 but not of nedd42 , the closest homolog of nedd41 in the mammalian genome , but the molecular mechanism underlying this isoform preference is unknown .
mtorc1 promotes global cap - dependent protein synthesis mainly by mediating the phosphorylation of eukaryotic initiation factor 4e binding protein 1 and 2 ( 4e - bp1 and 4e - bp2 ) .
4e - bps bind to eukaryotic initiation factor 4e ( elf4e ) to prevent the formation of protein initiation complex and protein translation .
phosphorylation of 4e - bps leads to decreased affinity of 4e - bps to eif4e .
this enables eif4e to be anchored to the 5-cap structure of mrnas , promotes the formation of protein initiation complex , and initiates protein synthesis . of note ,
the 5 untranslated region ( 5'utr ) of the nedd41 mrna ( genbank accession number : nm_010890 ) contains a pyrimidine - rich sequence stretch that is related to the 5 terminal oligopyrimidine ( 5top ) motif .
this 5top motif is important for anchoring elf4e to the 5-cap structure of mrnas , to direct the assembly of the translation machinery , and to initiate protein synthesis . the pyrimidine - rich sequence in the 5utr of nedd41 mrna may play a similar role as the 5top motif in initiating the translation of nedd41 mrnas in an mtorc1 activity - dependent manner ( fig .
further evidence supporting this model includes a study employing ribosome profiling to examine the translational efficiency of specific mrnas in the presence of an mtorc1 inhibitor , which showed that the translational efficiency of nedd41 mrna is reduced in non - neuronal cells upon mtorc1 inhibition . 

figure 1.model of the regulation of nedd41 translation by mtorc1 . in response to growth factor signaling ,
. elevated ptdinsp3 levels lead to the phosphorylation and activation of akt , which then activates mtorc1 .
phosphorylation of 4e - bps by mtorc1 reduces the binding of 4e - bps to eif4e , enabling eif4e to bind to the 5'utr of target mrnas and thus initiate protein synthesis .
the 5'utr of nedd41 mrna ( see sequence in the dialog box ) contains a pyrimidine - rich sequence stretch ( underlined ) after the putative transcriptional start site ( red ) , which is related to the 5 ' terminal oligopyrimidine ( 5'top ) motif .
this pyrimidine - rich sequence may play a key role in starting the translation of nedd41 mrnas in an mtorc1 activity - dependent manner .
nedd41 is a positive regulator of neurite growth and may have additional roles in regulating axon pathfinding , spine formation , and synaptic plasticity . 
 
in response to growth factor signaling , pi3k catalyzes the phosphorylation of ptdinsp2 to generate ptdinsp3 . pten converts ptdinsp3 back to ptdinp2 and thus antagonizes the effect of pi3k
. elevated ptdinsp3 levels lead to the phosphorylation and activation of akt , which then activates mtorc1 .
phosphorylation of 4e - bps by mtorc1 reduces the binding of 4e - bps to eif4e , enabling eif4e to bind to the 5'utr of target mrnas and thus initiate protein synthesis .
the 5'utr of nedd41 mrna ( see sequence in the dialog box ) contains a pyrimidine - rich sequence stretch ( underlined ) after the putative transcriptional start site ( red ) , which is related to the 5 ' terminal oligopyrimidine ( 5'top ) motif .
this pyrimidine - rich sequence may play a key role in starting the translation of nedd41 mrnas in an mtorc1 activity - dependent manner .
nedd41 is a positive regulator of neurite growth and may have additional roles in regulating axon pathfinding , spine formation , and synaptic plasticity .
accumulating evidence indicates crucial roles of local protein synthesis in various aspects of normal neuronal development and function , including axon guidance , spine formation , and synaptic plasticity .
all of these processes are highly dynamic and require spatially and temporally well - regulated and accurate changes in local protein levels in response to various stimuli .
locally regulated translation of mrnas provides an efficient way to spatially and temporally control local protein composition , which is of particular importance in distal neurites , where proteins synthesized at the soma may not be an economic source .
the finding that nedd41 expression is regulated at the translational level is compatible with the notion that nedd41 mrnas are major targets of the local translational machinery in neurons .
if so , it is very likely that nedd41 does not only regulate neurite growth regulation , as we reported previously , but may have important additional roles in axon guidance , spine formation , and synaptic plasticity .
indeed , drosophila melanogaster nedd4 regulates commisureless , which is an essential protein regulator of slit / robo signaling during axon pathfinding and midline crossing .
moreover , synaptic activation has been shown to cause a site - specific increase in nedd41 expression , which may mediate the ubiquitination and endocytosis of the ampa receptor subunit glua1 . in view of these findings , additional studies ,
ideally with higher spatiotemporal resolution , on how nedd41 expression is regulated in response to extracellular signals is very likely to provide further important insights into the physiological roles of nedd41 in neurons .
this work has been supported by grants from the german research foundation  ( spp1365/ka3423/11 ; to h.k . ) and the fritz thyssen foundation ( to h.k . ) .
 we found recently that mtorc1 regulates the biosynthesis of the ubiquitin e3 ligase nedd41 , but not the close homolog nedd42 . 
 this regulatory process plays a key role in promoting neurite growth in neurons of the mammalian central nervous system . the molecular mechanism underlying this rather specific regulation 
 likely involves a pyrimidine - rich sequence stretch near the putative transcriptional start site within the 5 untranslated region of the nedd41 mrna , which may play a crucial role in directing the assembly of the protein translation machinery . 
 we postulate that the nedd41 mrna is a major target of the local translation machinery within neurons that can be translated in a spatially and temporally controlled manner in response to various stimuli . based on this model , neuronal nedd41 
 may not only be involved in the regulation of neurite growth but also in axon guidance , spine formation , and synaptic plasticity . 