Phosphorylation of the discs large tumour suppressor protein controls its membrane localisation and enhances its susceptibility to HPV E6-induced degradation

Oncogene
P MassimiLawrence Banks

Abstract

The Discs Large (Dlg) protein is intimately involved in regulating cell polarity and cell proliferation, and is targeted by the high-risk Human Papillomavirus (HPV) E6 proteins for proteasome-mediated degradation. We show here that exposure of cells to osmotic shock induces the hyperphosphorylation of Dlg and its concomitant accumulation within the cell membrane at sites of cell contact, a process that requires an intact actin filament network. In addition, hyperphosphorylation of Dlg also renders it more susceptible to degradation induced by the HPV-18 E6 oncoprotein. Mutational analysis of Dlg identifies a region within the first 185 amino acids as being important for this, with phosphorylation on residue S158 being responsible for its enhanced targeting by the E6 oncoprotein. Using specific kinase inhibitors, we show that Jun N-terminal kinase (JNK) is in part responsible for this phosphorylation, and for the subsequent Dlg accumulation at sites of cell contact. These results further support the notion of a complex phosphorylation-dependent regulation of Dlg, both with respect to its precise cellular localisation and to its susceptibility to proteasome-mediated degradation.

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Citations

Jan 4, 2008·Histochemistry and Cell Biology·Christine Lavoie, Jacques Paiement
Sep 23, 2009·Biochemistry·Jana MarcetteKenneth E Prehoda
Apr 19, 2011·Acta Pharmacologica Sinica·Danila CoradiniSaro Oriana
Sep 1, 2007·Nature Cell Biology·Andreas Wodarz, Inke Näthke
Nov 24, 2012·Nature Reviews. Cancer·Lawrence BanksMiranda Thomas
Nov 26, 2008·Oncogene·P O HumbertH E Richardson
Nov 26, 2008·Oncogene·M ThomasL Banks
Jul 22, 2011·Journal of Virology·Ronald T Javier, Andrew P Rice
Oct 5, 2013·BioMed Research International·Kazunori NagasakaTomoyuki Fujii
Dec 5, 2012·Vaccine·John DoorbarMargaret A Stanley
Sep 19, 2012·Progress in Histochemistry and Cytochemistry·Fabio MarongiuEzio Laconi
Jul 21, 2010·Biochemical and Biophysical Research Communications·Francisco A Iñesta-VaqueraAna Cuenda
Aug 12, 2009·Experimental Cell Research·Martin BaumgartnerKarin Moelling
Apr 2, 2009·Journal of Molecular and Cellular Cardiology·Christian J PetersEric A Accili
Sep 17, 2008·Experimental Cell Research·Paola MassimiLawrence Banks
Mar 7, 2012·International Journal of Cancer. Journal International Du Cancer·Vanitha Krishna SubbaiahLawrence Banks
Jul 19, 2012·The FEBS Journal·David PimLawrence Banks
Mar 11, 2015·Reviews in Medical Virology·John DoorbarIsao Murakami
May 29, 2013·Virology·Scott B Vande Pol, Aloysius J Klingelhutz
Jun 21, 2011·Small GTPases·Kazunori NagasakaLawrence Banks
Nov 10, 2009·Virology·Hava LichtigLevana Sherman
Apr 14, 2016·PLoS Biology·Roberta NosedaAlessandra Bolino
May 21, 2015·Cancer Informatics·Wan-Hsin LinPanos Z Anastasiadis
Jan 17, 2013·Journal of Cell Science·Mojgan Padash-BarmchiVanessa J Auld
Dec 11, 2008·Journal of Cell Science·Nisha NarayanLawrence Banks

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