University of Algarve
Department of Biomedical Sciences and Medicine, Bld 7
Phone: +351 289 800 095 (internal extn. 7803)
The appropriate subcellular localization of proteins is crucially important to provide the physiological context for their cell function. Aberrant localization of proteins has been shown to contribute to the pathogenesis of many human diseases including metabolic, cardiovascular, neurodegenerative diseases and cancer and serves as valuable diagnostic or prognostic marker (Hung and Link, Journal Cell Science 124, 3381). The temporal and spatial regulation of protein localization has been shown to be particularly important for cancer stem-cells biology. Many important tumour suppressors and oncoproteins exert their functions in a specific cellular compartment. Aberrant localization of tumor suppressor proteins has been proposed to be a more generalized mechanism for their inactivation in human cancer. Hence, the therapeutic restoration of normal protein location targeting components of the signaling networks responsible for the inactivation of nuclear tumor suppressors has achieved considerable attention. Conversely, pharmaceutically induced mislocalization has been considered as a promising therapeutic strategy for targeting oncoproteins. There is a significant number of emerging technologies such as “high content screening” attempting to deal with the complexity of intact cells that allow for the unbiased characterization of critical nodal points in the signaling circuits that regulate protein localization. Understanding this process will likely be critical for identifying small molecule compounds or relevant therapeutic targets that might be exploited pharmaceutically to restore or interfere with protein localization and function.
Based on previous work characterizing regulatory signalling networks involved in subcellular translocation of the tumor suppressor FOXO3a, Dr Link's research will focus on the characterization of previously identified FOXO suppressors, the identification of novel indications of existing drugs that restore localization and function of FOXO proteins using image-based reprofiling and the application of the similar technological approaches to analyze regulatory signalling network involved in subcellular translocation of other tumor suppressors and oncoproteins.
BIO2006-02432 (Spanish MEC) (2006 – 2009) Targeting the PI3K/Akt signaling pathway: Identification of lead compounds and therapeutic targets.
BIO2002-00197 (Spanish MCyT) (2002 – 2005) Development of technologyplatforms to monitor the PI3K/Akt sgnaling pathway for anticancer drug discovery.
Selected Publications (2008-2012)
Kauselmann G., Dopazo A., and Link W. (2012) Identification of disease-relevant genes for molecularly targeted drug discovery Current Cancer Drug Targets, [Epub ahead of print]
Hung M.C. and Link W. (2011) Protein localization in disease and therapy. Journal Cell Science 124, 3381–3392.
Link W. (2011) Context–dependent therapeutic potential of FOXO proteins in oral squamous cell carcinoma Oral Oncology 47, 229-230
Link W. (2011) FOXO proteins as potential targets for anticancer therapy. Current Drug Targets 12, 1232-1234.
Evensen L., Link W. and Lorens J.B. (2010) Imaged-based high-throughput screening for anti-angiogenic drug discovery. Current Pharmaceutical Design, 16(35):3958-63.
Zanella F., Lorens JB and Link W. (2010) High Content Screening – Seeing is Believing. Trends Biotechnol. 28, 237-245. (Title story + Cover art)
Zanella F., Renner O., García B., Callejas S., Dopazo A., Peregrina S., Carnero A. and Link W. (2010) Human TRIB2 is a repressor of FOXO that contributes to the malignant phenotype of melanoma cells. Oncogene 29, 2973-2982.
Link W. (2010) Finding novel targets for anticancer therapy. European Pharmaceutical Review, 2, 27- 29.
Rabal O., Link W., García B, Bischoff J.R. and Oyarzabal J. (2010) An integrated one step system to extract, analyze and annotate all relevant information from image-based cell screening of chemical libraries. Mol. Biosyst., 6, 711 – 720.
Zanella F., Link W., Carnero A. (2010) Understanding FOXO, new views on old transcription factors. Curr Cancer Drug Targets 10, 135-146.
Evensen L., Micklem D.R., Link W. and Lorens JB (2010). A Novel Imaging-Based High-Throughput Screening Approach to Anti-Angiogenic Therapeutic Discovery. Cytometry A.
Link W., Oyarzabal J., Serrelde BG., Albarran MI, Rabal O., Cebriá A, Alfonso P, Fominaya J, Renner O, Peregrino S, Soilán D, Ceballos PA, Hernández AI, Lorenzo L, Pevarello P, Gonzalez-Granda T, Kurz G, Carnero A. and Bischoff J.R. (2009). Chemical interrogation of FOXO3a nuclear translocation identifies potent and selective inhibitors of phosphoinositide 3-kinases. J Biol Chem 284, 28392-28400.
Zanella F., Rosado A., García, G., Carnero A. and Link W. (2009). Using multiplexed regulation of luciferase activity and GFP translocation to screen for FOXO modulators. BMC Cell Biol. 10, 14.
Link W. (2009) Exploring the biological space of FOXO regulation: discovery of therapeutic targets and small molecule inhibitors for anticancer therapy. New Biotechnology, 25, S3-S3.
Zanella F., Rosado A., García, G., Blanco F, Carnero A. and Link W. (2008). Chemical genetic analysis of FOXO nuclear-cytoplasmic shuttling using Image-Based Cell Screening. ChemBioChem, 9, 2229-2237.
Rosado A., Zanella F., Garcia B., Carnero A. and Link W. (2008) A Dual-Color Fluorescence-Based Platform to Identify Selective Inhibitors of Akt Signaling. PLoS ONE 3(3), e1823.
Carnero A., Blanco-Aparicio C., Renner O. Link W. and Leal, J.F.M (2008). The PTEN/PI3K/AKT Signaling Pathway in Cancer, therapeutic Implications. Curr. Cancer Drug Targets. 8, 187-198.