Kun Ping Lu
Department of Medicine
Beth Israel Deaconess Medical Center
Center for Life Science Building, Room 0408
3 Blackfan Circle
Boston, MA 02115
Tel: (617) 735-2016
Fax: (617) 735-2050
Web Page: The Lu Lab Page
5 postdoctoral fellows, 1 graduate student
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 is a major regulatory mechanism in many physiological and pathological processes. Although these phosphorylation events had been long proposed to regulate protein function by inducing conformational changes, little was known about the nature, significance and regulation of such conformational changes until recently.
We have recently discovered a unique prolyl isomerase called Pin1 that specifically accelerated their conversions in certain proteins, leading us to propose a new signaling mechanism, whereby Pin1 catalytically regulates the conformation of its substrates after phosphorylation to control protein function. Indeed, subsequent studies have shown that such Pin1-catalyzed conformational regulation has profound impact on many key proteins in the regulation of diverse cellular processes including cell growth, genotoxic and other stress responses, immune response, stem cell development, neuronal differentiation and survival. 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 a growing number of pathological conditions, including cancer, Alzheimer’s disease, aging, microbial infection and autoimmune disorders. Moreover, modulating Pin1 activity in these diseases would offer an attractive new therapeutic option.
In addition, we have identified the telomeric protein Pin2/TRF1 and its interacting proteins, PinX1-4, which play an important role in telomere maintenance. 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. These studies yield new insights into telomere maintenance, cell growth control and oncogenesis, and may lead to the development of new anticancer therapy. Therefore, the recent results from our laboratory have established a new paradigm in cell signaling and telomere maintenance, uncovered new pathogenic mechanisms and also pointed to novel therapeutic strategies for human diseases.
- Liou, Y.-C., Sun, A., Ryo, A., Zhou, X. Z., Yu, Z.-X., Huang, H.-K., Bronson, R., Bing, G., Li, X., Hunter, T. and Lu, K. P. 2003. Role of the prolyl isomerase Pin1 in protecting against age-dependent neurodegeneration. Nature 424: 556-561.
- Pastorino, L., Sun, A., Lu, P. J., Zhou, X. Z., Balastik, M., Finn, G., Wulf, G., Lim, J., Li, S. H., Li, X., Xia, W., Nicholson, L. and Lu, K. P. 2006, The prolyl isomerase Pin1 regulates amyloid precursor protein processing and Amyloid-beta production. Nature 440: 528-534.
- Lu, K. P. and Zhou, X. Z., 2007, The phosphorylation-specific prolyl isomerase Pin1: A pivotal new twist in phosphorylation signalling and disease. Nature Reviews Mol. Cell. Biol. 8: 904-916.
- Lim, J., Balastik, M., Lee, T. H. Liou, Y. C., Sun, A., Finn, G., Pastorino, L. Lee, V. M.-Y. and Lu, K. P., 2007, Opposite impact of Pin1 on the tauopathy phenotype induced by Alzheimer’s wild-type tau and FTDP-17 P301L tau. J. Clin. Invest. 118:1877-1889.
- 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.
BBS webpage updated 12/02/2009