Kun Ping Lu
Department of Medicine
Center for Life Science, Room 0408
3 Blackfan Circle
Boston, MA 02115
Tel: 617-735-2016
Fax: 617-735-2050
Email: klu@bidmc.harvard.edu
Lab Members: 5 postdoctoral fellows, 1 graduate student
Visit my lab page here.
Our laboratory is interested in elucidating the regulation of cell signaling and telomere maintenance, and in determining their role in the development and treatment of human disease.
Protein phosphorylation on serines or threonines preceding a proline (pSer/Thr-Pro) is a major regulatory mechanism in many physiological and pathological processes. We have previously discovered a unique prolyl isomerase called Pin1 that specifically catalyzes cis-trans isomerization of specific pSer/Thr-Pro motifs in certain proteins. Recent studies from our lab and others have shown that such Pin1-catalyzed conformational regulation has profound impact on many key proteins in the regulation of diverse cellular processes. We have now developed cis and trans conformation-specific antibodies to directly visualize these protein conformational changes after phosphorylation and to dissect their function and regulation under physiological and pathological conditions. Pin1 has emerged as a novel molecular timer that modulates its multiple targets at various steps of a given cellular process to synergistically control the amplitude and duration of a cellular response or process. Importantly, Pin1 is tightly regulated and its deregulation has a pivotal role in certain diseases, notably age-related disease such as cancer and Alzheimer’s disease. We are developing small molecules or antibodies to modulate Pin1 activity or its substrate conformations, which might offer attractive new therapeutic options for these major diseases.
In addition, we have identified the telomeric protein Pin2/TRF1 and its interacting proteins, PinX1-4, which play an important role in telomere maintenance and tumorigenesis. Telomeres are critical for maintaining genomic stability, and their deregulation has been implicated in cancer and aging. Pin2/TRF1 controls telomere length and regulates mitotic progression. PinX1 is a conserved endogenous telomerase catalytic inhibitor and a potent tumor suppressor essential for chromosome stability.
In short, the recent studies from our laboratory have established novel signal transduction mechanisms, uncovered new pathogenic mechanisms and also points to potentially novel therapeutic strategies for cancer, autoimmune disorders, and Alzheimer’s disease.
References:
Lee, T. H., Lim, J., Tun-Kyi, A., Finn, G., Shi, R., Balastik, M., Pastorino, L., Wulf, Zhou, X. Z. and Lu, K. P. 2009, Essential role of Pin1 in the regulation of TRF1 stability and telomere maintenance. Nature Cell. Biol. 11: 97-105.
Tun-Kyi, A., Finn, G., Greenwood, A., Nowak, M., Lee, T. H., Asara, J. M., Tsokos, G. C., Fitzgerald, K., Israel, E., Li, X., Exley, M., Nicholson, L. K. and Lu, K. P. 2011, Essential role for the prolyl isomerase Pin1 in Toll-like receptor signaling and type I interferon-mediated immunity. Nature Immunol. 12: 733-741.
Zhou, X. Z., Huang P., Lee, T. H., Shi, R., Lu, G. Bronson, R. and Lu, K. P. 2011, The telomerase inhibitor PinX1 is a major haploinsufficent tumor suppressor essential for chromosome stability in mice. J. Clin. Invest. 121: 1266-1282 (The Cover Story).
Min, S. H., Lau, A. W., Lee, T. H., Inuzuka, H., Wei, S. Huang, P., Shaik, S. Lee, D. Y. Finn, G., Balastik, M., Chen, C. H., Luo, M., Tron, A. E., DeCaprio, J. A., Zhou, X. Z., Wei, W. and Lu, K. P. 2012. Negative regulation of the stability and tumor suppressor function of Fbw7 by the Pin1 prolyl isomerase. Mol. Cell 46: 771-783.
Nakamura, K., Greenwood, A., Binder, L., Bigio, E. H., Denial, S. J., Nicholson, L., Zhou, X. Z. and Lu, K. P. 2012. Proline isomer-specific antibodies reveal the early pathogenic tau conformation in Alzheimer's disease. Cell 149: 232-244.
For a complete listing of publications click here.
Last Update: 8/10/2012