Harald Stenmark (director)

Harald_Stenmark

Institute for Cancer Research, Oslo University Hospital, and Institute for Clinical Medicine, University of Oslo
http://ous-research.no/stenmark/

 

BACKGROUND

The cells in our body are compartmentalized by membranes, which are not static but undergo continuous budding, fission, fusion and remodelling events, collectively referred to as membrane dynamics. Such dynamics control most essential cellular functions, including signal transduction, cytoskeletal organization, polarity, migration, intracellular transport of lipids and macromolecules, and cell division. Not surprisingly, genetic or acquired aberrations in cellular membrane dynamics are associated with a number of diseases, including cancer.

King Olav V’s cancer research prize for 2014 to Harald A. Stenmark

 

 

RESEARCH

In our group we are interested in the connections between membrane dynamics and cancer development. Our starting point has been studies of a lipid that controls membrane dynamics, phosphatidylinositol 3-phosphate (PI3P). We discovered a conserved domain that binds specifically to this lipid, the FYVE domain [1;2], and we have been studying the functions of several FYVE domain-containing proteins [3-5]. One of these is HRS, an endosomal protein that mediates sorting of ubiquitinated membrane proteins, such as activated growth factor receptors, to the lumen of the lysosome [6]. HRS is in complex with a related protein, STAM, and together these constitute the ESCRT-0 subcomplex of the endosomal sorting complex required for transport (ESCRT) machinery [7]. Originally discovered for its function in endosomal protein sorting and biogenesis of multivesicular endosomes (MVEs), components of this machinery have turned out to have numerous functions in the cell, all related to regulation of membrane dynamics. One example is the abscission step of cytokinesis (the final stage of cell division whereby the two daughter cells become separated), and we have identified an ESCRT-interacting protein called ANCHR that serves a key role in the abscission checkpoint that halts cytokinetic abscission when lagging chromosomes are detected in the intercellular bridge [8]. We recently found that components of the ESCRT machinery function to seal the reformed nuclear envelope during mitotic exit, thereby ensuring nuclear integrity and safeguarding the genome [9].

 

MODEL SYSTEMS AND METHODS

As in vitro model systems we use a large number of human cell lines derived from cancers and normal tissues, and organoids of epithelial cells grown in matrigel. As in vivo model we employ zebrafish and the fruit fly Drosophila melanogaster. We use a number of advanced genetic and molecular biology methods to turn specific gene functions on and off, and as readouts we use both biochemical assays and molecular imaging. In particular, our group has experience in advanced light and electron microscopy. Light imaging methods include confocal microscopy, SIM and STORM super-resolution microscopy, live imaging, selective plane illumination microscopy (SPIM), and high-content imaging. Electron microscopy methods include conventional plastic embedding electron microscopy, immunoelectron microscopy, electron tomography and correlative light and electron microscopy (CLEM). Our group is scientifically responsible for the core facilities in Advanced Light Microscopy and Electron Microscopy of the Institute for Cancer Research.

 

CURRENT PROJECTS include (with project co-ordinators in parentheses):

– ER-endosome contact sites in endosome positioning, cell signalling, and protrusion outgrowth (Camilla Raiborg)

– Mechanisms and physiological importance of cytokinesis regulation in vivo (Kaisa Haglund)

– Mechanisms of receptor tyrosine kinases and autophagy in tumour growth and invasion (Tor Erik Rusten)

– Mechanisms and cellular importance of aggregate autophagy (Andreas Brech)

– Mechanisms and importance of ESCRT-mediated genome safeguarding during cell division (Coen Campsteijn)

– PI3P-binding proteins in regulation of early endocytic membrane traffic (Kay O. Schink)

– The “destruction complex” in regulation of Wnt signalling, and its pharmacological targeting in cancer (Eva M. Wenzel)

 

SELECTED PUBLICATIONS

[1]    Stenmark,H., Aasland,R., Toh,B.H., & D’Arrigo,A. (1996) Endosomal localization of the autoantigen EEA1 is mediated by a zinc-binding FYVE finger. J. Biol. Chem. 271, 24048-24054.

[2]    Gaullier,J.-M., Simonsen,A., D’Arrigo,A., Bremnes,B., Aasland,R., & Stenmark,H. (1998) FYVE fingers bind PtdIns(3)P. Nature 394, 432-433.

[3]    Simonsen,A., Lippé,R., Christoforidis,S., Gaullier,J.-M., Brech,A., Callaghan,J., Toh,B.-H., Murphy,C., Zerial,M., & Stenmark,H. (1998) EEA1 links PI(3)K function to Rab5 regulation of endosome fusion. Nature 394, 494-498.

[4]    Sagona,A.P., Nezis,I.P., Pedersen,N.M., Liestol,K., Poulton,J., Rusten,T.E., Skotheim,R.I., Raiborg,C., & Stenmark,H. (2010) PtdIns(3)P controls cytokinesis through KIF13A-mediated recruitment of FYVE-CENT to the midbody. Nat. Cell Biol. 12, 362-371.

[5]    Raiborg,C., Wenzel,E.M., Pedersen,N.M., Olsvik,H., Schink,K.O., Schultz,S.W., Vietri,M., Nisi,V., Bucci,C., Brech,A., Johansen,T., & Stenmark,H. (2015) Repeated ER-endosome contacts promote endosome translocation and neurite outgrowth. Nature 520, 234-238.

From the news: Nature article from Camilla Raiborg: Formation of cellular protrusions

[6]    Raiborg,C., Bache,K.G., Gillooly,D.J., Madshus,I.H., Stang,E., & Stenmark,H. (2002) Hrs sorts ubiquitinated proteins into clathrin-coated microdomains of early endosomes. Nat. Cell Biol. 4, 394-398.

[7]    Raiborg,C. & Stenmark,H. (2009) The ESCRT machinery in endosomal sorting of ubiquitylated membrane proteins. Nature 458, 445-452.

[8]    Thoresen,S.B., Campsteijn,C., Vietri,M., Schink,K.O., Liestol,K., Andersen,J.S., Raiborg,C., & Stenmark,H. (2014) ANCHR mediates Aurora-B-dependent abscission checkpoint control through retention of VPS4. Nat. Cell Biol. 16, 550-560.

From the news:
Article about work in the Stenmark group on www.nrk.no: The long road to success
Two new research dissemination contributions from OUH/CCB scientists
Nature Cell Biology article from Sigrid B. Thoresen

[9]    Vietri,M., Schink,K.O., Campsteijn,C., Wegner,C.S., Schultz,S.W., Christ,L., Thoresen,S.B., Brech,A., Raiborg,C., & Stenmark,H. (2015) Spastin and ESCRT-III coordinate mitotic spindle disassembly and nuclear envelope sealing. Nature 522, 231-235.

From the news:
Paper from OUS/CCB researchers dedicated commentary articles in both Nature and Science

Nature article from Marina Vietri: Sealing holes in the nuclear envelope as a mechanism to protect the genome