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Cell Biology and Stem Cells Unit

Laboratory 2

The Wnt signalling pathway plays an important role in cell growth and differentiation and is frequently activated in cancer. Our goals are to understand how Wnts, their antagonists and their effectors control cell growth and differentiation and to use the technological platforms at CIC bioGUNE to characterise the cellular responses to Wnt ligands. We study these aspects in two contexts - neuronal differentiation and prostate cancer (PCa) progression.

We have analysed Wnt gene expression during retinoic acid induction of neural differentiation of human embryonal carcinoma (hEC) cells; three Wnts were identified that might play roles in this process, one of which is Wnt-11. We have also examined Wnt gene expression in PCa and found that Wnt-11 is upregulated in hormone-refractory tumour cells. We are presently studying how Wnt-11 and other Wnts control cell survival and differentiation. In addition, we have characterised the sFRP and Dickkopf families of secreted Wnt antagonists in these cell systems, and we are currently studying the function of Dkk-3 in more detail. Finally, we have characterised the Wnt effectors axin and glycogen synthase kinase-3 (GSK-3), which are key regulators of Wnt/beta-catenin and other signalling pathways. We have identified phosphorylation sites in axin that appear to play a role in the regulation of GSK-3 activity, and we have uncovered unique properties of beta2, the brain-specific isoform of GSK-3. Our hope is that these studies will lead to the discovery of new treatments for the many diseases caused by the aberrant activation of Wnt and GSK-3 signals.

COLLABORATIONS

• Phillip Gordon-Weeks (MRC Centre for Developmental Neurobiology, Kings College London)
• María del Mar Vivanco (CIC bioGUNE)
• Jonathan Waxman (Imperial College London)
• Christof Niehrs (DKFZ, Heidelberg)
  
• Akira Kikuchi (Hiroshima University)

Principal Investigator

Laboratory members

Publications

Sunters A, Armstrong VJ, Zaman G, Kypta RM, Kawano Y, Lanyon LE, Price JS;

Mechanotransduction in osteoblastic cells involves strain-regulated ER-mediated control of IGF-1 receptor sensitivity to ambient IGF, leading to PI3-kinase/Akt-dependent Wnt/LRP5 receptor-independent activation of beta-catenin signaling

. Journal of Biological Chemistry 285, 12 8743-58 (2010)

Zafira Castaño, Phillip R. Gordon-Weeks and Robert M. Kypta; The neuron-specfic isoform of GSK-3 is required for axon growth.. Journal of Neurochemistry 113, 1 117-130 (2010)

Uysal-Onganer P, Kawano Y, Caro M, Walker MM, Diez S, Darrington RS, Waxman J, Kypta RM; Wnt-11 promotes neuroendocrine-like differentiation, survival and migration of prostate cancer cells. Molecular Cancer 9, 55 (2010)

Kypta RM; Wnt signaling. Encyclopedia of Cancer 2nd edition (2009)

Kawano Y, Diez S, Uysal-Onganer P, Darrington RS, Waxman J, Kypta RM; Secreted Frizzled-related protein-1 is a negative regulator of androgen receptor activity in prostate cancer. British Journal of Cancer 100, 7 1165-1174 (2009)

Zafira Castano, Robert M. Kypta; Housekeeping Proteins: Limitations as References During Neuronal Differentiation. The Open Neuroscience Journal 2, 36-40 (2008)

Kypta, RM; GSK-3 inhibitors and their potential in the treatment of Alzheimer's disease. EXPERT OPIN THER PAT. 15, 1315-1331 (2005)

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