From molecules to tissue architecture

Research

 Morphogenesis in development and tissue maintenance requires an intricate balance between cell-cell interactions, cell-proliferation, cell migration and differentiation. Loss of the co-ordination between these processes prohibits proper development and is also involved in tumour formation. The long-term goal of research in my laboratory is to understand how cellular adhesion, migration, and cell division are regulated in concert during development and differentiation and how changes in these processes contribute to tumour formation.

My particular focus is the adenomatous polyposis coli protein, a large cytoplasmic protein that has been implicated in a variety of basic cellular processes including cell migration, cell adhesion, and proliferation. APC binds to beta-catenin and regulates its intracellular concentration. Beta-catenin is an important mediator of cell adhesion and also plays a role in regulating the activity of specific transcription factors. APC also interacts directly and indirectly with cytoskeletal proteins and regulates their stability. Its multi-functional nature places APC at the interface between regulation of cellular architecture and differentiation programs and this may explain the high penetrance of APC mutations, particularly in the intestinal tract: APC mutations constitute an extremely early stage of inherited as well as sporadic colon cancer. In addition, patients with somatic deletions in one of the APC alleles, have an increased risk for developing brain tumours and other epithelial abnormalities.

The aim of work in my laboratory is to determine the molecular mechanisms that govern the role of the APC protein in cell migration, adhesion and division and includes investigating the relationship between different protein interactions of APC in vivo. The experimental approaches we use include whole tissue, cultured cells, in vitro assays combined with cellular and molecular biology techniques as well as high-resolution fluorescence microscopy.

Publications

1. Nathke I., and Rocha S. "Antagonistic crosstalk between APC and HIF-1alpha."  Cell Cycle, 2011 15;10(10): 1545-7.

2. Newton I.P., Kenneth N.S., Appleton P.L., Näthke I, Rocha S. “APC and HIF-1 alpha have an antagonistic connection.” Mol Biol Cell, 2010 21:3630-3638 published online 10.1091/mbc.E10-04-0312.

3. Jones,S.E.M., Joice, P., Cochrane, L., Thoresen, I. Quyn, A., Näthke, I. “Is Familial Adenomatous Polyposis Associated with Sensorineural Hearing Loss?" (2010) Intl. J. Audiology, 49:762-764

4. Radulescu S., Ridgway R.A., Appleton P., Kroboth K., Patel S., Woodgett J., Taylor S., Näthke I.S., Sansom O.J. “Defining the role of APC in the mitotic spindle checkpoint in vivo: APC-deficient cells are resistant to Taxol” (2010) Oncogene Aug 23. [Epub ahead of print]

5. Dikovskaya D., Li Z., Newton I.P., Davidson I., Hutchins J.R., Kalab P., Clarke P.R., Näthke I.S, “Microtubule assembly by the Apc protein is regulated by importin-beta--RanGTP.” (2010) J Cell Sci. 123:736-746

6. Quyn A.J., Appleton P.L., Carey F.A., Steele R.J., Barker N., Clevers H., Ridgway R.A., Sansom O.J., Näthke I.S. “Spindle orientation bias in gut epithelial stem cell compartments is lost in precancerous tissues”, (2010) Cell Stem Cell. 6:175-181.

7. Buchert M., Athineos D., Abud H.E., Burke Z.D., Faux M.C., Samuel M.S., Jarnicki A.G., Winbanks C.E., Newton I.P., Meniel V.S., Suzuki H., Stacker S.A., Näthke I.S., Tosh D., Huelsken J., Clarke A.R., Heath J.K., Sansom O.J., Ernst M., “Genetic dissection of differential signalling threshold requirement for the Wnt/beta-catenin pathway in vivo” (2010) PLoS Genet. 6(1):e1000816

8. Appleton P.L., Quyn A.J., Swift S., Näthke I. “Preparation of wholemount mouse intestine for high-resolution three-dimensional imaging using 2-photon microscopy”, (2009) J. Microscopy, 234:196-204.
9. Li, Z., Kroboth, K, Newton, I.P., Näthke, I., “Novel self-association of the adenomatous polyposis coli (APC) molecule affects APC clusters and cell migration”, (2008) J. Cell Science 121:1916-1925.
10. Dikovskaya, D., Schiffman, D., Newton, I., Oakley, A., Kroboth, K., Jamieson, T.J., Meniel V., Clarke, A., Sansom, O., Näthke, I., “ Loss of APC induces polyploidy due to a combination of defects in mitotic spindles, mitotic spindle checkpoint, and apoptosis”, (2007) J. Cell Biol. 15: 183-195.
11. Kroboth, K., Newton, I.P., Zumbrunn, J., Li, Z., Kita, K., Waterman-Storer, C.M., Näthke, I.S., “Lack of adenomatous polyposis coli protein correlates with a decrease in cell migration and overall changes in microtubule stability”, (2007) Mol. Biol. Cell.18:910-918.
12. Schiffmann, D.A., Dikovskaya, D., Appleton, P.L., Newton, I., Allan, C., Goldberg, I.G., Näthke, I.S., “Open Microscopy Environment & FindSpots: integrating image informatics with quantitative multidimensional image analysis”, (2006) Biotechniques, 41(2):199-208.
13. Kita, K., Wittmann, T., Näthke, I.S., Waterman-Storer, C.M., “APC protein modulates local microtubule assembly/disassembly dynamics independently of EB1”, (2006) Mol. Biol. Cell, 17:2331-2345.
14. Penman, G., Leung, L, and Näthke, I.S., “APC is present in different protein complexes with distinct functions”, (2005) J. Cell Science, 118: 4741-4750.
15. Li, Z. and Näthke, I.S., “Tumour-associated NH2-terminal fragments are the most stable part of the adenomatous polyposis coli protein and can be regulated by interactions with COOH-terminal domains”, (2005), Cancer Research, 65: 5195-5204.
16. Brocado, M, Näthke, I.S., Henderson, B.R., “Redefining the subcellular location and transport of APC: new insights using a panel of antibodies”, (2005) EMBO Rep., 6: 184-190.
17. Sansom, O.J., Reed, K., Hayes, A.J., Ireland, H., Brinkmann, H., Newton, I.P., Batlle, E., Simon-Assmann, P., Hans Clevers, H., Näthke, I.S., Clarke, A.R, Winton, D.J., (2004) “Loss of APC in vivo immediately perturbs Wnt signaling, differentiation, and migration”, Genes&Development, 18: 1385-1390.
18. Dikovskaya, D., Newton I.P., Näthke, I.S., (2004) “The Adenomatous Polyposis Coli protein is required for the formation of robust spindles formed in CSF Xenopus extracts”, Mol. Biol. Cell, 15: 2978-2991.
19. Mogensen, M.M, Tucker, J.B., Mackie, J.B., Prescott, A.R., Näthke, I.S., (2002) “The Adenomatous Polyposis Coli protein unambiguously localises to microtubule plus ends and is involved in establishing parallel arrays of microtubule bundles in highly polarised epithelial cells”, J. Cell Biology, 157: 1041-1048.
20. Zumbrunn, J., Inoshita, K., Hyman, A.A., Näthke, I.S. (2001) “Binding of the Adenomatous Polyposis Coli protein to microtubules increases microtubule stability and is regulated by GSK3ÿ phosphorylation”, Current Biology 11, 44-49.
21. Kaplan, K.B., Burds,, A.A., Swedlow, J.R., Bekir, S.S., Sorger, P.K., Näthke , I.S. (2001) “A novel role for the Adenomatous Polyposis Coli protein in chromosome segregation”, Nature Cell Biology, 3:429-432.
22. Ritchie, T., Zhou, W., McKinstry, E., Hosch, M., Zhang, Y., Näthke, I.S., Engelhardt, J.F. (2001) “Developmental Expression of catenins and associated proteins during submucosal gland morphogenesis in the airway”, Experimental Lung Research, 27, 121-141.
23. Thomas, G.M., Frame, S., Goedert, M., Näthke, I.S. Polakis, P., Cohen, P. (1999) “A GSK3-binding peptide from FRAT1 selectively inhibits the GSK3ÿ–catalysed phosphorylation of Axin and ÿ-catenin”, FEBS Lett. 458, 247-251.
24. Näthke, I.S., Adams , C.L., Polakis, P., Sellin, J.H., Nelson, W.J. (1996) “The Adenomatous Polyposis Coli (APC) tumor suppressor protein localizes to plasma membrane sites involved in active cell migration”, J. Cell Biol. 134, 165-179.

Invited reviews and bookchapters:

1. Näthke, I. and McCartney, B. (2008), editors “APC proteins” Landes Bioscience.
2. McCartney, B.M, and Näthke, I.S. (2008) "Cell regulation by the Apc protein; Apc as master regulator of epithelia", Curr. Opin, Cell Biol., 20:186-193.
3. Wodarz, A. and Näthke, I. (2007) "Cell polarity in development and cancer", Nature Cell Biology, 9:1016-1024.
4. Näthke, I. (2006), “Cytoskeleton out of the cupboard: how changes in the cytoskeleton induced by loss of APC contribute to colon cancer” Nat. Cancer Reviews, 6: 967-974. (Cover image)
5. Näthke, I. and Nelson, W.J. (2005) editors of “Cell-to-cell contact and extracellular matrix: Laying down the rules for proper cell behavior”, Curr Opin Cell Biol. 17:443-445.
6. Näthke I. (2005) “Relationship between the role of the adenomatous polyposis coli protein in colon cancer and its contribution to cytoskeletal regulation”, Biochem Soc Trans. 33 (Pt 4): 694-697.
7. Näthke, I., (2004) "The Adenomatous Polyposis Coli protein: the Achilles Heel of the gut epithelium." Ann. Rev. Cell & Develop. Biol., 20: 337-366.
8. Näthke, I. (2004) “Cell Science at a Glance: The Adenomatous Polyposis Coli protein”, J. Cell Sci., 117: 4873-4875.
9. Näthke, I., (2002) “Tracking APC’s attachment to the cytoskeleton”, ELSO Gazette: e-magazine of the European Life Scientist Organization , Issue 8 (January, 2002).
10. Allan, V. and Näthke, I.S. (2001) “Catch and pull a microtubule: getting a grasp on the cortex”, Nature Cell Biology, 3, E226-228.
11. Dikovskaya, D. Zumbrunn, J., Penman, G.A., Näthke, I.S. (2001) “The Adenomatous Polyposis Coli protein: in the limelight out at the edge”, Trends in Cell Biology, 11, 378-384.
12. Näthke, I.S. (1999) “The Adenomatous Polyposis Coli Protein” Molecular Pathology 52, 169-173.
13. Barth, A.I.M., Näthke,, I.S., Nelson, W.J. (1997) “Cadherins, catenins and APC protein: interplay between cytoskeletal complexes and signaling pathway”, Curr. Opin. Cell Biol., 9, 683-690.
14. Näthke, I.S., Barth, A.I.M., Nelson, W.J. “Role for the tumor suppressor Adenomatous Polyposis Coli protein in epithelial cell migration and adhesion: a hypothesis”, in Cytoskeletal-Membrane Interactions and Signal Transduction, (1997), 103-110.