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• W774201769 abstract "Deubiquitylases (DUBs) have been implicated in the regulation of cellsignaling processes. However, the role of DUBs in the regulation of theEpidermal growth factor receptor (EGFR) signaling is not completelyunderstood. This study has aimed to identify DUBs involved in the regulationof EGFR signaling and downstream cascades. The first part of this study hascharacterized the role of the DUB USP15 in the regulation of the mitogenactivated protein kinase (MAPK) cascade, a pathway downstream of EGFR.An interaction between USP15 and the MAPK negative regulator BRAP hadbeen previously reported. When we tested the USP15 depletion phenotype onMAPK signaling we observed a paradoxical decrease in MAPK activation.Examination of upstream components of the MAPK cascade revealed adecrease in the levels of the CRAF kinase following USP15 depletion.Concordant depletion of CRAF also caused a reduction in MAPK activation,showing that depletion of CRAF phenocopied that of USP15. This workdemonstrated that USP15 has a dual role in the regulation of the MAPKthrough BRAP and CRAF. The dominant signaling effect in the cell linesstudied is through maintenance of CRAF levels.We employed a previously characterized GFP-DUB library to identifyDUBs that exhibited EGF dependent distributions. One such DUB, USP46,exhibited MAPK dependent recruitment onto multi-vesicular bodies (MVB). Tofurther characterize USP46 we generated a set of cell lines expressing GFPUSP46and catalytically inactive GFP-USP46-C44S using the Flp-in system.While the Flp-in cells lines did not exhibit the same EGF dependentrecruitment onto the MVB compartment, they did localize to Saponin resistantpunctate structures. Furthermore, I observed differential activation ofdownstream EGFR signaling pathways that USP46 may play anundetermined role in EGF signaling. We combining stable isotope labeling ofamino acids in culture (SILAC) with immuno-precipitation (IP) to quantitativelyidentify interactors of USP46 using mass spectrometry. We identified a13number of candidate interactors and confirmed a novel interaction betweenUSP46 and FBXO11 using western blotting.Next we aimed to identify DUBs that regulate the retrograde traffickingpathway from the MVB to the trans Golgi network (TGN). We used thelocalization of the cation independent mannose 6-phosphate receptor (CIM6PR)as readout of the retrograde trafficking. CI-M6PR constitutivelyrecycles from the TGN to the endo-lysosomal pathway, delivering newlysynthesized acid hydrolases, required for degradative action of the lysosome.Depletion of USP8 trapped CI-M6PR in aberrant endosomes and caused aconcomitant missorting of the acid hydrolase, Cathepsin D. Cathepsin D isactivated through limited proteolysis in the acidic environment of the endolysosomalpathway. Depletion of USP8 caused a decrease in the maturecellular form of Cathepsin D. The mislocalization of CI-M6PR could berescued by re-expression of GFP-USP8. The activated EGFR is degraded viathe lysosome and depletion of USP8 has been demonstrated to cause a delayin the degradation of EGFR. The results presented here suggest that thedecrease in active acid hydrolases observed in USP8 depleted cells, maycontribute to the delay in EGFR degradation." @default.
• W774201769 created "2016-06-24" @default.
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• W774201769 date "2013-10-01" @default.
• W774201769 modified "2023-09-27" @default.
• W774201769 title "The role of reversible ubiquitylation in EGF signalling" @default.
• W774201769 hasPublicationYear "2013" @default.
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