title: A role for the ubiquitin ligase Nedd4 in membrane sorting of LAPTM4 proteins.
abstract: BACKGROUND
  The lysosome associated protein transmembrane (LAPTM) family is comprised of three members: LAPTM5, LAPTM4a and LAPTM4b, with the latter previously shown to be overexpressed in numerous cancers. While we had demonstrated earlier the requirement of the E3 ubiquitin ligase Nedd4 for LAPTM5 sorting to lysosomes, the regulation of sorting of LAPTM4 proteins is less clear.
  
  
  RESULTS
  Here we show that LAPTM4a and LAPTM4b are localized to the lysosome, but unique to LAPTM4b, a fraction of it is present at the plasma membrane and its overexpression induces the formation of actin-based membrane protrusions. We demonstrate that LAPTM4s, like LAPTM5, are able to co-immunoprecipitate with the E3 ubiquitin ligase Nedd4, an interaction that is dependent on LAPTM4 PY motifs and plays a role in membrane sorting. Accordingly, in Nedd4 knockout mouse embryonic fibroblasts (MEFs), LAPTM4a and LAPTM4b show reduced lysosomal localization. Moreover, lack of PY motifs leads to enhanced missorting of LAPTM4b to the plasma membrane instead of the lysosome.
  
  
  CONCLUSIONS
  These results suggest that while some requisites of LAPTM5 lysosomal sorting are conserved among LAPTM4 proteins, LAPTM4a and LAPTM4b have also developed distinct sorting requirements.
authors.affiliation: Program in Cell Biology, The Hospital for Sick Children, Biochemistry Department, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Ruth
authors.initials: R
authors.lastname: Milkereit
authors.forename: Daniela
authors.initials: D
authors.lastname: Rotin
mesh_terms: D000818:Animals; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism*; D002478:Cells, Cultured; D002846:Chromatography, Affinity; D056827:Endosomal Sorting Complexes Required for Transport / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D017874:Immediate-Early Proteins / Q000235:genetics / Q000378:metabolism; D008247:Lysosomes / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D026901:Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018613:Microscopy, Confocal; D000075702:Nedd4 Ubiquitin Protein Ligases; D015513:Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D021381:Protein Transport / Q000235:genetics / Q000502:physiology; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: D056827:Endosomal Sorting Complexes Required for Transport; D017874:Immediate-Early Proteins; C569342:LAPTM4A protein, human; C477083:LAPTM4B protein, human; C099283:Laptm4a protein, mouse; C484408:Laptm5 protein, mouse; D008565:Membrane Proteins; D026901:Membrane Transport Proteins; D015513:Oncogene Proteins; C100848:LAPTM5 protein, human; D000075702:Nedd4 Ubiquitin Protein Ligases; C000618483:Nedd4 protein, human; C000618461:Nedd4l protein, mouse; D044767:Ubiquitin-Protein Ligases
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