Harald Stenmark

Dr. Harald Stenmark
Intracellular Communication 
Dept. of Biochemistry
Institute for Cancer Research
Oslo University Hospital, 
The Norwegian Radium Hospital
stenmark@ulrik.uio.no
Tel +47 22 78 18 18

 

 

ACTIVITIES

Receptor signalling guides the maintenance and fate of stem cells and their progenitors, including renewal, proliferation and choice of differentiation pathways. Dysregulated receptor signalling is associated with oncogenesis and is probably a central cue in the development of cancer stem cells.

Our group studies receptor signalling and how it is attenuated by endocytosis. In particular, we have been studying epidermal growth factor (EGF), a strong proliferative signal, and  how EGF receptors become endocytosed and degraded after EGF binding. Ligand binding causes ubiquitination of EGF receptors, and we have identified and characterized a ubiquitin-binding endosomal machinery that recognizes ubiquitinated receptors in endosomes and mediates their sorting to lysosomes. Preliminary studies suggest that components of this machinery serve as tumour suppressors, and we are now performing further studies to characterize the functional mechanisms of endosomal sorting complexes in receptor downregulation and tumour suppression.

As model systems we use cultured human cell lines as well as Drosophila models for cell signalling and oncogenesis. Confocal microscopy is central in our work, and in addition to characterizing stem cell relevant signalling pathways we will also contribute to the SFI project by characterizing the intracellular localization and trafficking of relevant cancer stem cell markers.

 

 

GROUP MEMBERS
active in CAST 

 

Harald Stenmark
Professor, group leader

Tor Erik Rusten
Scientist, project leader

Lene Malerød
Post doc

 

Viola Lobert
Post doc

 

 

STATUS 2013

The group works on a molecular dissection of the Wnt signaling pathway, with focus on components of the endocytic pathway.
Recent evidence suggests that endosomal sequestration of inhibitory factors is a key event in Wnt signaling, and the group is exploring this further as a possible target for therapy.
The group is also collaborating with the Krauss -group on understanding the dynamics of “destruction complexes” involved in negative regulation of Wnt signaling, and how these respond to inhibitors of the Wnt pathway.

 

SELECTED PUBLICATIONS

Kostaras E
Sflomos GPedersen NMStenmark HFotsis TMurphy C
SARA and RNF11 interact with each other and ESCRT-0 core proteins and regulate degradative EGFR trafficking
Oncogene (in press) 
PubMed 23222715

Rusten TEFilimonenko MRodahl LMStenmark HSimonsen A
ESCRTing autophagic clearance of aggregating proteins
Autophagy4 (2) (in press)
PubMed 18204305

Bostad MBerg KHøgset ASkarpen EStenmark HSelbo PK (2013)
Photochemical internalization (PCI) of immunotoxins targeting CD133 is specific and highly potent at femtomolar levels in cells with cancer stem cell properties
J Control Release168 (3)317-26
PubMed 23567040

Eikenes ÅHBrech AStenmark HHaglund K (2013)
Spatiotemporal control of Cindr at ring canals during incomplete cytokinesis in the Drosophila male germline
Dev Biol377 (1)9-20
PubMed 23499247

Oppelt ALobert VHHaglund KMackey AMRameh LELiestøl KSchink KOPedersen NMWenzel EMHaugsten EMBrech ARusten TEStenmark HWesche J(2013)
Production of phosphatidylinositol 5-phosphate via PIKfyve and MTMR3 regulates cell migration
EMBO Rep14 (1)57-64
PubMed 23154468

Pedersen NMRaiborg CBrech ASkarpen ERoxrud IPlatta HWLiestøl KStenmark H (2012)
The PtdIns3P-binding protein Phafin 2 mediates epidermal growth factor receptor degradation by promoting endosome fusion
Traffic13 (11)1547-63
PubMed 22816767

Platta HWAbrahamsen HThoresen SBStenmark H (2012)
Nedd4-dependent lysine-11-linked polyubiquitination of the tumour suppressor Beclin 1
Biochem J441 (1)399-406
PubMed 21936852

Lobert VHStenmark H (2012)
The ESCRT machinery mediates polarization of fibroblasts through regulation of myosin light chain
J Cell Sci125 (Pt 1)29-36
PubMed 22266905

Lind GERaiborg CDanielsen SARognum TOThiis-Evensen EHoff GNesbakken AStenmark HLothe RA (2011)
SPG20, a novel biomarker for early detection of colorectal cancer, encodes a regulator of cytokinesis
Oncogene30 (37)3967-78
PubMed 21499309

Malerød LPedersen NMSem Wegner CELobert VHLeithe EBrech ARivedal ELiestøl KStenmark H (2011)
Cargo-dependent degradation of ESCRT-I as a feedback mechanism to modulate endosomal sorting
Traffic12 (9)1211-26
PubMed 21564451

Platta HWStenmark H (2011)
Endocytosis and signaling
Curr Opin Cell Biol23 (4)393-403
PubMed 21474295

Sagona APNezis IPBache KGHaglund KBakken ACSkotheim RIStenmark H (2011)
A tumor-associated mutation of FYVE-CENT prevents its interaction with Beclin 1 and interferes with cytokinesis
PLoS One6 (3)e17086
PubMed 21455500

Haglund KNezis IPStenmark H (2011)
Structure and functions of stable intercellular bridges formed by incomplete cytokinesis during development
Commun Integr Biol4 (1)1-9
PubMed 21509167

Thoresen SBPedersen NMLiestøl KStenmark H (2010)
A phosphatidylinositol 3-kinase class III sub-complex containing VPS15, VPS34, Beclin 1, UVRAG and BIF-1 regulates cytokinesis and degradative endocytic traffic
Exp Cell Res316 (20)3368-78
PubMed 20643123

Stenmark H (2010)
The Sir Hans Krebs Lecture. How a lipid mediates tumour suppression. Delivered on 29 June 2010 at the 35th FEBS Congress in Gothenburg, Sweden
FEBS J277 (23)4837-48
PubMed 20977678

Lobert VHStenmark H (2010)
Ubiquitination of α-integrin cytoplasmic tails
Commun Integr Biol3 (6)583-5
PubMed 21331246

Stuffers SMalerød LSchink KOCorvera SStenmark HBrech A (2010)
Time-resolved ultrastructural detection of phosphatidylinositol 3-phosphate
J Histochem Cytochem58 (11)1025-32
PubMed 20713985

Nezis IPShravage BVSagona APJohansen TBaehrecke EHStenmark H (2010)
Autophagy as a trigger for cell death: autophagic degradation of inhibitor of apoptosis dBruce controls DNA fragmentation during late oogenesis in Drosophila
Autophagy6 (8)1214-5
PubMed 20935512

Husebye HAune MHStenvik JSamstad ESkjeldal FHalaas ONilsen NJStenmark HLatz ELien EMollnes TEBakke OEspevik T (2010)
The Rab11a GTPase controls Toll-like receptor 4-induced activation of interferon regulatory factor-3 on phagosomes
Immunity33 (4)583-96
PubMed 20933442

Knævelsrud HAhlquist TMerok MANesbakken AStenmark HLothe RASimonsen A (2010)
UVRAG mutations associated with microsatellite unstable colon cancer do not affect autophagy
Autophagy6 (7)863-70
PubMed 20724836

Hansson EMLanner FDas DMutvei AMarklund UEricson JFarnebo FStumm GStenmark HAndersson ERLendahl U (2010)
Control of Notch-ligand endocytosis by ligand-receptor interaction
J Cell Sci123 (Pt 17)2931-42
PubMed 20720151

Nezis IPShravage BVSagona APLamark TBjørkøy GJohansen TRusten TEBrech ABaehrecke EHStenmark H (2010)
Autophagic degradation of dBruce controls DNA fragmentation in nurse cells during late Drosophila melanogaster oogenesis
J Cell Biol190 (4)523-31
PubMed 20713604

Lobert VHBrech APedersen NMWesche JOppelt AMalerød LStenmark H (2010)
Ubiquitination of alpha 5 beta 1 integrin controls fibroblast migration through lysosomal degradation of fibronectin-integrin complexes
Dev Cell19 (1)148-59
PubMed 20643357

Haglund KNezis IPLemus DGrabbe CWesche JLiestøl KDikic IPalmer RStenmark H (2010)
Cindr interacts with anillin to control cytokinesis in Drosophila melanogaster
Curr Biol20 (10)944-50
PubMed 20451383

Filimonenko MIsakson PFinley KDAnderson MJeong HMelia TJBartlett BJMyers KMBirkeland HCLamark TKrainc DBrech AStenmark HSimonsen A,Yamamoto A (2010)
The selective macroautophagic degradation of aggregated proteins requires the PI3P-binding protein Alfy
Mol Cell38 (2)265-79
PubMed 20417604

Clausen THLamark TIsakson PFinley KLarsen KBBrech AØvervatn AStenmark HBjørkøy GSimonsen AJohansen T (2010)
p62/SQSTM1 and ALFY interact to facilitate the formation of p62 bodies/ALIS and their degradation by autophagy
Autophagy6 (3)330-44
PubMed 20168092

Sagona APNezis IPPedersen NMLiestøl KPoulton JRusten TESkotheim RIRaiborg CStenmark H (2010)
PtdIns(3)P controls cytokinesis through KIF13A-mediated recruitment of FYVE-CENT to the midbody
Nat Cell Biol12 (4)362-71
PubMed 20208530

Wegner CSMalerød LPedersen NMProgida CBakke OStenmark HBrech A (2010)
Ultrastructural characterization of giant endosomes induced by GTPase-deficient Rab5
Histochem Cell Biol133 (1)41-55
PubMed 19830447

Leithe EKjenseth ASirnes SStenmark HBrech ARivedal E (2009)
Ubiquitylation of the gap junction protein connexin-43 signals its trafficking from early endosomes to lysosomes in a process mediated by Hrs and Tsg101
J Cell Sci122 (Pt 21)3883-93
PubMed 19808888

Roxrud IRaiborg CGilfillan GDStrømme PStenmark H (2009)
Dual degradation mechanisms ensure disposal of NHE6 mutant protein associated with neurological disease
Exp Cell Res315 (17)3014-27
PubMed 19619532

Vaccari TRusten TEMenut LNezis IPBrech AStenmark HBilder D (2009)
Comparative analysis of ESCRT-I, ESCRT-II and ESCRT-III function in Drosophila by efficient isolation of ESCRT mutants
J Cell Sci122 (Pt 14)2413-23
PubMed 19571114

Rusten TEStenmark H (2009)
How do ESCRT proteins control autophagy?
J Cell Sci122 (Pt 13)2179-83
PubMed 19535733

Stuffers SSem Wegner CStenmark HBrech A (2009)
Multivesicular endosome biogenesis in the absence of ESCRTs
Traffic10 (7)925-37
PubMed 19490536

Nezis IPLamark TVelentzas ADRusten TEBjørkøy GJohansen TPapassideri ISStravopodis DJMargaritis LHStenmark HBrech A (2009)
Cell death during Drosophila melanogaster early oogenesis is mediated through autophagy
Autophagy5 (3)298-302
PubMed 19066465

Rodahl LMHaglund KSem-Jacobsen CWendler FVincent JPLindmo KRusten TEStenmark H (2009)
Disruption of Vps4 and JNK function in Drosophila causes tumour growth
PLoS One4 (2)e4354
PubMed 19194501

Rodahl LMStuffers SLobert VHStenmark H (2009)
The role of ESCRT proteins in attenuation of cell signalling
Biochem Soc Trans37 (Pt 1)137-42
PubMed 19143618

Morrison HADionne HRusten TEBrech AFisher WWPfeiffer BDCelniker SEStenmark HBilder D (2008)
Regulation of early endosomal entry by the Drosophila tumor suppressors Rabenosyn and Vps45
Mol Biol Cell19 (10)4167-76
PubMed 18685079

Umebayashi KStenmark HYoshimori T (2008)
Ubc4/5 and c-Cbl continue to ubiquitinate EGF receptor after internalization to facilitate polyubiquitination and degradation
Mol Biol Cell19 (8)3454-62
PubMed 18508924

Lindmo KBrech AFinley KDGaumer SContamine DRusten TEStenmark H (2008)
The PI 3-kinase regulator Vps15 is required for autophagic clearance of protein aggregates
Autophagy4 (4)500-6
PubMed 18326940

Gilfillan GDSelmer KKRoxrud ISmith RKyllerman MEiklid KKroken MMattingsdal MEgeland TStenmark HSjøholm HServer ASamuelsson LChristianson ATarpey PWhibley AStratton MRFutreal PATeague JEdkins SGecz JTurner GRaymond FLSchwartz CStevenson RE et al. (2008)
SLC9A6 mutations cause X-linked mental retardation, microcephaly, epilepsy, and ataxia, a phenotype mimicking Angelman syndrome
Am J Hum Genet82 (4)1003-10
PubMed 18342287

Nezis IPSimonsen ASagona APFinley KGaumer SContamine DRusten TEStenmark HBrech A (2008)
Ref(2)P, the Drosophila melanogaster homologue of mammalian p62, is required for the formation of protein aggregates in adult brain
J Cell Biol180 (6)1065-71
PubMed 18347073

Roxrud IRaiborg CPedersen NMStang EStenmark H (2008)
An endosomally localized isoform of Eps15 interacts with Hrs to mediate degradation of epidermal growth factor receptor
J Cell Biol180 (6)1205-18
PubMed 18362181

Rusten TEFilimonenko MRodahl LMStenmark HSimonsen A (2008)
ESCRTing autophagic clearance of aggregating proteins
Autophagy4 (2)233-236

Raiborg CMalerød LPedersen NMStenmark H (2008)
Differential functions of Hrs and ESCRT proteins in endocytic membrane trafficking
Exp Cell Res314 (4)801-13
PubMed 18031739

Bergeland THaugen LLandsverk OJStenmark HBakke O (2008)
Cell-cycle-dependent binding kinetics for the early endosomal tethering factor EEA1
EMBO Rep9 (2)171-8
PubMed 18188183

Filimonenko MStuffers SRaiborg CYamamoto AMalerød LFisher EMIsaacs ABrech AStenmark HSimonsen A (2007)
Functional multivesicular bodies are required for autophagic clearance of protein aggregates associated with neurodegenerative disease
J Cell Biol179 (3)485-500
PubMed 17984323

Progida CMalerød LStuffers SBrech ABucci CStenmark H (2007)
RILP is required for the proper morphology and function of late endosomes
J Cell Sci120 (Pt 21)3729-37
PubMed 17959629

Malerød LStuffers SBrech AStenmark H (2007)
Vps22/EAP30 in ESCRT-II mediates endosomal sorting of growth factor and chemokine receptors destined for lysosomal degradation
Traffic8 (11)1617-29
PubMed 17714434

Rusten TEVaccari TLindmo KRodahl LMNezis IPSem-Jacobsen CWendler FVincent JPBrech ABilder DStenmark H (2007)
ESCRTs and Fab1 regulate distinct steps of autophagy
Curr Biol17 (20)1817-25
PubMed 17935992

Feugaing DDTammi REchtermeyer FGStenmark HKresse HSmollich MSchönherr EKiesel LGötte M (2007)
Endocytosis of the dermatan sulfate proteoglycan decorin utilizes multiple pathways and is modulated by epidermal growth factor receptor signaling
Biochimie89 (5)637-57
PubMed 17335953

 

Harald Stenmark laboratory