Abstract
It is becoming increasingly apparent that a complex bar code underlies the quantitative aspects of extracellular signal regulation. Cell type-specific and context-dependent transcriptional programs are triggered by sophisticated nanomachinery consisting of HECT enzymes which monitor signal generation, transduction and termination. How the HECT enzymes safeguard spatiotemporal organization was a fundamental question towards understanding the process of protein degradation and its functions in diverse biological processes. In this review we will dismantle how HECT E3 enzymes regulate the trafficking of many receptors, channels and transporters as well as how HECT enzymes negatively regulate each other. There is accumulating evidence that suggests an undeniable role of HECT enzymes in regulating mediators of the Wnt signal-transduction cascade. By contrast, little is known about the crosstalk of HECT enzymes with ATM and TRAIL in prostate cancer, but several hints have emerged. This review provides a broader snapshot for studying multiple pathways in parallel, rather than as separate entities.
Similar content being viewed by others
References
Albesa M, Grilo LS, Gavillet B, Abriel H (2011) Nedd4-2-dependent ubiquitylation and regulation of the cardiac potassium channel hERG1. J Mol Cell Cardiol 51(1):90–98
Alesutan I, Föller M, Sopjani M, Dërmaku-Sopjani M, Zelenak C, Fröhlich H, Velic A, Fraser S, Kemp BE, Seebohm G, Völkl H, Lang F (2011a) Inhibition of the heterotetrameric K+ channel KCNQ1/KCNE1 by the AMP-activated protein kinase. Mol Membr Biol 28:79–89
Alesutan I, Munoz C, Sopjani M, Dërmaku-Sopjani M, Michael D, Fraser S, Kemp BE, Seebohm G, Föller M, Lang F (2011b) Inhibition of Kir2.1 (KCNJ2) by the AMP-activated protein kinase. Biochem Biophys Res Commun 408:505–510
Alzamora R, Gong F, Rondanino C, Lee JK, Smolak C, Pastor-Soler NM, Hallows KR (2010) AMP-activated protein kinase inhibits KCNQ1 channels through regulation of the ubiquitin ligase Nedd4-2 in renal epithelial cells. Am J Physiol Renal Physiol 299:F1308–F1319
Andrews PS, Schneider S, Yang E, Michaels M, Chen H, Tang J, Emkey R (2010) Identification of substrates of SMURF1 ubiquitin ligase activity utilizing protein microarrays. Assay Drug Dev Technol 8(4):471–487
Aragón E, Goerner N, Zaromytidou AI, Xi Q, Escobedo A, Massagué J, Macias MJ (2011) A Smad action turnover switch operated by WW domain readers of a phosphoserine code. Genes Dev 25(12):1275–1288
Cui Y, He S, Xing C, Lu K, Wang J, Xing G, Meng A, Jia S, He F, Zhang L (2011) SCF(FBXL15) regulates BMP signalling by directing the degradation of HECT-type ubiquitin ligase Smurf1. EMBO J 30(13):2675–2689
Diakov A, Nesterov V, Mokrushina M, Rauh R, Korbmacher C (2010) Protein kinase B alpha (PKBα) stimulates the epithelial sodium channel (ENaC) heterologously expressed in Xenopus laevis oocytes by two distinct mechanisms. Cell Physiol Biochem 26:913–924
Farooqi AA, Mansoor Q, Rana A, Manzoor Mashhadi T, Imran M, Naqi SA, Rehman Z-u, Bhatti S (2011a) SMURF and NEDD4 interference offers therapeutic potential in chaperoning genome integrity. J Exp Integr Med 1:43–50
Farooqi AA, Fayyaz S, Mansoor Q, Ismail M, Bhatti S (2011b) Towards TRAIL to silencing of SMURF and NEDD4: FLIP is flopped. J Exp Integr Med 1:111–116
Fukunaga E, Inoue Y, Komiya S, Horiguchi K, Goto K, Saitoh M, Miyazawa K, Koinuma D, Hanyu A, Imamura T (2008) Smurf2 induces ubiquitin-dependent degradation of Smurf1 to prevent migration of breast cancer cells. J Biol Chem 283(51):35660–35667
Gasser A, Cheng X, Gilmore ES, Tyrrell L, Waxman SG, Dib-Hajj SD (2010) Two Nedd4-binding motifs underlie modulation of sodium channel Nav1.6 by p38 MAPK. J Biol Chem 285:26149–26161
Grabbe C, Husnjak K, Dikic I (2011) The spatial and temporal organization of ubiquitin networks. Nat Rev Mol Cell Biol 12:295–307
Guo X, Shen S, Song S, He S, Cui Y, Xing G, Wang J, Yin Y, Fan L, He F, Zhang L (2011) The E3 ligase Smurf1 regulates Wolfram syndrome protein stability at the endoplasmic reticulum. J Biol Chem 286(20):18037–18047
Heise CJ, Xu BE, Deaton SL, Cha SK, Cheng CJ, Earnest S, Sengupta S, Juang YC, Stippec S, Xu Y, Zhao Y, Huang CL, Cobb MH (2010) Serum and glucocorticoid-induced kinase (SGK) 1 and the epithelial sodium channel are regulated by multiple with no lysine (WNK) family members. J Biol Chem 285:25161–25167
Hu XY, Xu YM, Fu Q, Yu JJ, Huang J (2009) Nedd4L expression is downregulated in prostate cancer compared to benign prostatic hyperplasia. Eur J Surg Oncol 35:527–531
Kalkan T, Iwasaki Y, Park CY, Thomsen GH (2009) Tumor necrosis factor-receptor-associated factor-4 is a positive regulator of transforming growth factor-beta signaling that affects neural crest formation. Mol Biol Cell 20:3436–3450
Ke Y, Butt AG, Swart M, Liu YF, McDonald FJ (2010) COMMD1 downregulates the epithelial sodium channel through Nedd4-2. Am J Physiol Renal Physiol 298:F1445–F1456
Kim S, Jho EH (2010) The protein stability of Axin, a negative regulator of Wnt signaling, is regulated by Smad ubiquitination regulatory factor 2 (Smurf2). J Biol Chem 285(47):36420–36426
Lee IH, Song SH, Campbell CR, Kumar S, Cook DI, Dinudom A (2011) Regulation of the epithelial Na+ channel by the RH domain of G protein-coupled receptor kinase, GRK2, and Galphaq/11. J Biol Chem 286(22):19259–19269
Li H, Xu LL, Masuda K, Raymundo E, McLeod DG, Dobi A, Srivastava S (2008) A feedback loop between the androgen receptor and a NEDD4-binding protein, PMEPA1, in prostate cancer cells. J Biol Chem 283:28988–28995
Lin A, Hou Q, Jarzylo L, Amato S, Gilbert J, Shang F, Man HY (2011) Nedd4-mediated AMPA receptor ubiquitination regulates receptor turnover and trafficking. J Neurochem. doi:10.1111/j.1471-4159.2011.07221.x
Lu K, Li P, Zhang M, Xing G, Li X, Zhou W, Bartlam M, Zhang L, Rao Z, He F (2011) Pivotal role of the C2 domain of the Smurf1 ubiquitin ligase in substrate selection. J Biol Chem 286(19):16861–16870
Moore FE, Osmundson EC, Koblinski J, Pugacheva E, Golemis EA, Ray D, Kiyokawa H (2010) The WW-HECT protein Smurf2 interacts with the docking protein NEDD9/HEF1 for Aurora A activation. Cell Div 8(5):22
Nie J, Wu M, Wang J, Xing G, He F, Zhang L (2010) REGgamma proteasome mediates degradation of the ubiquitin ligase Smurf1. FEBS Lett 584(14):3021–3027
Oberfeld B, Ruffieux-Daidié D, Vitagliano JJ, Pos KM, Verrey F, Staub O (2011) Ubiquitin-specific protease 2-45 (Usp2-45) binds to epithelial Na+ channel (ENaC)-ubiquitylating enzyme Nedd4-2. Am J Physiol Renal Physiol 301(1):F189–F196
Ogunjimi AA, Wiesner S, Briant DJ, Varelas X, Sicheri F, Forman-Kay J, Wrana JL (2010) The ubiquitin binding region of the Smurf HECT domain facilitates polyubiquitylation and binding of ubiquitylated substrates. J Biol Chem 285(9):6308–6315
Qi H, Grenier J, Fournier A, Labrie C (2003) Androgens differentially regulate the expression of NEDD4L transcripts in LNCaP human prostate cancer cells. Mol Cell Endocrinol 210:51–62
Ray D, Ahsan A, Helman A, Chen G, Hegde A, Gurjar SR, Zhao L, Kiyokawa H, Beer DG, Lawrence TS, Nyati MK (2011) Regulation of EGFR protein stability by the HECT-type ubiquitin ligase SMURF2. Neoplasia 13(7):570–578
Renauld S, Tremblay K, Ait-Benichou S, Simoneau-Roy M, Garneau H, Staub O, Chraïbi A (2010) Stimulation of ENaC activity by rosiglitazone is PPARγ-dependent and correlates with SGK1 expression increase. J Memb Biol 236:259–270
Rougier JS, Albesa M, Abriel H, Viard P (2011) Neuronal precursor cell-expressed developmentally down-regulated 4-1 (NEDD4-1) controls the sorting of newly-synthesized Cav1.2 calcium channels. J Biol Chem 286(11):8829–8838
Ruffieux-Daidié D, Staub O (2011) Intracellular ubiquitylation of the epithelial Na+ channel controls extracellular proteolytic channel activation via conformational change. J Biol Chem 286:2416–2424
Schwarz LA, Hall BJ, Patrick GN (2010) Activity-dependent ubiquitination of GluA1 mediates a distinct AMPA receptor endocytosis and sorting pathway. J Neurosci 30:16718–16729
Sherk AB, Frigo DE, Schnackenberg CG, Bray JD, Laping NJ, Trizna W, Hammond M, Patterson JR, Thompson SK, Kazmin D, Norris JD, McDonnell DP (2008) Development of a small-molecule serum- and glucocorticoid-regulated kinase-1 antagonist and its evaluation as a prostate cancer therapeutic. Cancer Res 68:7475–7483
Sidoryk-Wegrzynowicz M, Lee ES, Ni M, Aschner M (2010) Manganese-induced downregulation of astroglial glutamine transporter SNAT3 involves ubiquitin-mediated proteolytic system. Glia 58:1905–1912
Sidoryk-Wegrzynowicz M, Lee E, Mingwei N, Aschner M (2011) Disruption of astrocytic glutamine turnover by manganese is mediated by the protein kinase C pathway. Glia. doi:10.1002/glia.21219
Tang Y, Liu Z, Zhao L, Clemens TL, Cao X (2008) Smad7 stabilizes beta-catenin binding to E-cadherin complex and promotes cell–cell adhesion. J Biol Chem 283(35):23956–23963
Tian M, Bai C, Lin Q, Lin H, Liu M, Ding F, Wang HR (2011) Binding of RhoA by the C2 domain of E3 ligase Smurf1 is essential for Smurf1-regulated RhoA ubiquitination and cell protrusive activity. FEBS Lett 585(14):2199–2204
Vina-Vilaseca A, Sorkin A (2010) Lysine 63-linked polyubiquitination of the dopamine transporter requires WW3 and WW4 domains of Nedd4-2 and UBE2D ubiquitin-conjugating enzymes. J Biol Chem 285:7645–7656
Vina-Vilaseca A, Bender-Sigel J, Sorkina T, Closs EI, Sorkin A (2011) Protein kinase C dependent ubiquitination and clathrin-mediated endocytosis of the cationic amino acid transporter CAT-1. J Biol Chem 286(10):8697–8706
Wiemuth D, Lott JS, Ly K, Ke Y, Teesdale-Spittle P, Snyder PM, McDonald FJ (2010) Interaction of serum- and glucocorticoid regulated kinase 1 (SGK1) with the WW-domains of Nedd4-2 is required for epithelial sodium channel regulation. PLoS One 5:e12163
Wu Q, Huang JH, Sampson ER, Kim KO, Zuscik MJ, O’Keefe RJ, Chen D, Rosier RN (2009) Smurf2 induces degradation of GSK-3beta and upregulates beta-catenin in chondrocytes: a potential mechanism for Smurf2-induced degeneration of articular cartilage. Exp Cell Res 315(14):2386–2398
Wu K, Yan H, Fang L, Wang X, Pfleger C, Jiang X, Huang L, Pan ZQ (2011) Mono-ubiquitination drives nuclear export of the human Dcn1-like protein hDCNL1. J Biol Chem (In press)
Xu LL, Shi Y, Petrovics G, Sun C, Makarem M, Zhang W, Sesterhenn IA, McLeod DG, Sun L, Moul JW, Srivastava S (2003) PMEPA1, an androgen-regulated NEDD4-binding protein, exhibits cell growth inhibitory function and decreased expression during prostate cancer progression. Cancer Res 63:4299–4304
Zaro BW, Yang YY, Hang HC, Pratt MR (2011) Chemical reporters for fluorescent detection and identification of O-GlcNAc-modified proteins reveal glycosylation of the ubiquitin ligase NEDD4–1. Proc Natl Acad Sci USA 108(20):8146–8151
Zhang W, Na T, Wu G, Jing H, Peng JB (2010) Down-regulation of intestinal apical calcium entry channel TRPV6 by ubiquitin E3 ligase Nedd4-2. J Biol Chem 285:36586–36596
Zheng X, Morrison AC, Feingold E, Turner ST, Ferrell RE (2011) Association between NEDD4L gene and sodium lithium countertransport. Am J Hypertens 24:145–148
Zhou R, Kabra R, Olson DR, Piper RC, Snyder PM (2010) Hrs controls sorting of the epithelial Na+ channel between endosomal degradation and recycling pathways. J Biol Chem 285:30523–30530
Author information
Authors and Affiliations
Corresponding authors
Rights and permissions
About this article
Cite this article
Farooqi, A.A., Waseem, M.S., Riaz, A.M. et al. SMURF and NEDD4: Sharp Shooters Monitor the Gate Keepers and Ion Traffic Controllers of Lead Astray Cell. J Membrane Biol 244, 1–8 (2011). https://doi.org/10.1007/s00232-011-9394-2
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00232-011-9394-2