Photo of Kun Ping Lu,  MD, PhD

Kun Ping Lu, MD, PhD

Beth Israel Deaconess Medical Center

Beth Israel Deaconess Medical Center
Phone: (617) 735-2016
Fax: (617) 735-2050


klu@bidmc.harvard.edu

Kun Ping Lu, MD, PhD

Beth Israel Deaconess Medical Center

EDUCATIONAL TITLES

  • Professor, Medicine, Harvard Medical School

DF/HCC PROGRAM AFFILIATION

Research Abstract

My laboratory has pioneered in elucidating the role of Pin1-catalyzed cis-trans conformational regulation after proline-directed phosphorylation in cell signaling in health and disease, and also identified novel Pin1-targeted therapies in cancer, autoimmune disorders, traumatic brain injury and Alzheimer’s disease.

Protein phosphorylation regulates diverse cellular processes in health and disease. Our lab has discovered a unique enzyme called Pin1 that introduces a pivotal new twist in phosphorylation signaling by converting phosphorylated proteins between two functionally distinct conformations, cis and trans. Deregulation of this novel signaling mechanism leads to accumulation of proteins in the pathogenic conformations, thereby having profound impact on the development of many diseases, especially those related to aging or stress such as Alzheimer’s disease, traumatic brain injury, cancer and autoimmune disorders. More significantly, our lab has recently developed innovative antibody technology that can specifically detect and eliminate these pathogenic conformations, such as cis tau protein, a major early driver of neurodegeneration, for early diagnosis and treatment of brain injury and Alzheimer’s disease. Our recent development of Pin1 high-throughput drug screens has identified a series of new Pin1 inhibitors, including all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) as synergistic Pin1 inhibitors to block multiple cancer-driving pathways and eliminate cancer stem cells. Notably, the ATO+ATRA combination has revolutionized APL treatment from highly fatal to highly curable, with good safety profiles, but their drug targets remain elusive. Our results identify Pin1 as a major target for ATRA+ATO, and suggest that Pin1 inhibitors such as ATRA and ATO may be used to overcome drug resistance by blocking numerous cancer-driving pathways and eliminating cancer stem cells. These discoveries have suggested a promising new paradigm for the development of diagnostics and therapeutics that specifically target the pathogenic protein conformations in a wide range of diseases.

The current projects focus on translating our new discoveries into clinical products for improving human health, notably Pin1 inhibitors to stop multiple cancer-driving pathways and conformation-specific antibody for early diagnosis and treatment of Alzheimer’s disease and traumatic brain injury.

Publications

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  • Kozono S, Lin YM, Seo HS, Pinch B, Lian X, Qiu C, Herbert MK, Chen CH, Tan L, Gao ZJ, Massefski W, Doctor ZM, Jackson BP, Chen Y, Dhe-Paganon S, Lu KP, Zhou XZ. Arsenic targets Pin1 and cooperates with retinoic acid to inhibit cancer-driving pathways and tumor-initiating cells. Nat Commun 2018; 9:3069. PubMed
  • Lian X, Lin YM, Kozono S, Herbert MK, Li X, Yuan X, Guo J, Guo Y, Tang M, Lin J, Huang Y, Wang B, Qiu C, Tsai CY, Xie J, Gao ZJ, Wu Y, Liu H, Zhou XZ, Lu KP, Chen Y. Pin1 inhibition exerts potent activity against acute myeloid leukemia through blocking multiple cancer-driving pathways. J Hematol Oncol 2018; 11:73. PubMed
  • Yang D, Luo W, Wang J, Zheng M, Liao XH, Zhang N, Lu W, Wang L, Chen AZ, Wu WG, Liu H, Wang SB, Zhou XZ, Lu KP. A novel controlled release formulation of the Pin1 inhibitor ATRA to improve liver cancer therapy by simultaneously blocking multiple cancer pathways. J Control Release 2018; 269:405-422. PubMed
  • Frain L, Swanson D, Cho K, Gagnon D, Lu KP, Betensky RA, Driver J. Association of cancer and Alzheimer's disease risk in a national cohort of veterans. Alzheimers Dement 2017. PubMed
  • Zheng M, Xu H, Liao XH, Chen CP, Zhang AL, Lu W, Wang L, Yang D, Wang J, Liu H, Zhou XZ, Lu KP. Inhibition of the prolyl isomerase Pin1 enhances the ability of sorafenib to induce cell death and inhibit tumor growth in hepatocellular carcinoma. 2017; 8:29771-29784. PubMed
  • Rogals MJ, Greenwood AI, Kwon J, Lu KP, Nicholson LK. Neighboring phosphoSer-Pro motifs in the undefined domain of IRAK1 impart bivalent advantage for Pin1 binding. FEBS J 2016; 283:4528-4548. PubMed
  • Min SH, Zhou XZ, Lu KP. The role of Pin1 in the development and treatment of cancer. Arch Pharm Res 2016. PubMed
  • Zhou XZ, Lu KP. The isomerase PIN1 controls numerous cancer-driving pathways and is a unique drug target. Nat Rev Cancer 2016; 16:463-78. PubMed
  • Chae U, Park SJ, Kim B, Suo W, Min JS, Lee JH, Park SH, Lee AH, Lu KP, Lee DS, Min SH. Critical role of XBP1 in cancer signaling is regulated by PIN1. Biochem J 2016. PubMed
  • Balastik M, Zhou XZ, Alberich-Jorda M, Weissova R, Žiak J, Pazyra-Murphy MF, Cosker KE, Machonova O, Kozmikova I, Chen CH, Pastorino L, Asara JM, Cole A, Sutherland C, Segal RA, Lu KP. Prolyl Isomerase Pin1 Regulates Axon Guidance by Stabilizing CRMP2A Selectively in Distal Axons. Cell Rep 2015; 13:812-28. PubMed
  • Hilton BA, Li Z, Musich PR, Wang H, Cartwright BM, Serrano M, Zhou XZ, Lu KP, Zou Y. ATR Plays a Direct Antiapoptotic Role at Mitochondria, which Is Regulated by Prolyl Isomerase Pin1. Mol Cell 2015; 60:35-46. PubMed
  • Wei S, Kozono S, Kats L, Nechama M, Li W, Guarnerio J, Luo M, You MH, Yao Y, Kondo A, Hu H, Bozkurt G, Moerke NJ, Cao S, Reschke M, Chen CH, Rego EM, Lo-Coco F, Cantley LC, Lee TH, Wu H, Zhang Y, Pandolfi PP, Zhou XZ, Lu KP. Active Pin1 is a key target of all-trans retinoic acid in acute promyelocytic leukemia and breast cancer. Nat Med 2015; 21:457-66. PubMed
  • Luo ML, Gong C, Chen CH, Hu H, Huang P, Zheng M, Yao Y, Wei S, Wulf G, Lieberman J, Zhou XZ, Song E, Lu KP. The Rab2A GTPase promotes breast cancer stem cells and tumorigenesis via Erk signaling activation. Cell Rep 2015. PubMed
  • Jalouli M, Déry MA, Lafleur VN, Lamalice L, Zhou XZ, Lu KP, Richard DE. The prolyl isomerase Pin1 regulates hypoxia-inducible transcription factor (HIF) activity. Cell Signal 2014. PubMed
  • Luo ML, Gong C, Chen CH, Lee DY, Hu H, Huang P, Yao Y, Guo W, Reinhardt F, Wulf G, Lieberman J, Zhou XZ, Song E, Lu KP. Prolyl isomerase Pin1 acts downstream of miR200c to promote cancer stem-like cell traits in breast cancer. Cancer Res 2014. PubMed
  • Liu P, Begley M, Michowski W, Inuzuka H, Ginzberg M, Gao D, Tsou P, Gan W, Papa A, Kim BM, Wan L, Singh A, Zhai B, Yuan M, Wang Z, Gygi SP, Lee TH, Lu KP, Toker A, Pandolfi PP, Asara JM, Kirschner MW, Sicinski P, Cantley L, Wei W. Cell-cycle-regulated activation of Akt kinase by phosphorylation at its carboxyl terminus. Nature 2014; 508:541-5. PubMed
  • De S, Greenwood AI, Rogals MJ, Kovrigin EL, Lu KP, Nicholson LK. Complete thermodynamic and kinetic characterization of the isomer-specific interaction between Pin1-WW domain and the amyloid precursor protein cytoplasmic tail phosphorylated at Thr668. Biochemistry 2013. PubMed
  • Nakamura K, Kosugi I, Lee DY, Hafner A, Sinclair DA, Ryo A, Lu KP. Prolyl isomerase Pin1 regulates neuronal differentiation via β-catenin. Mol Cell Biol 2012; 32:2966-78. PubMed
  • Min SH, Lau AW, Lee TH, Inuzuka H, Wei S, Huang P, Shaik S, Lee DY, Finn G, Balastik M, Chen CH, Luo M, Tron AE, Decaprio JA, Zhou XZ, Wei W, Lu KP. Negative regulation of the stability and tumor suppressor function of Fbw7 by the Pin1 prolyl isomerase. Mol Cell 2012; 46:771-83. PubMed
  • Luo T, Yu J, Nguyen J, Wang CR, Bristow RG, Jaffray DA, Zhou XZ, Lu KP, Lu QB. Electron transfer-based combination therapy of cisplatin with tetramethyl-p-phenylenediamine for ovarian, cervical, and lung cancers. Proc Natl Acad Sci U S A 2012; 109:10175-80. PubMed
  • Zhou XZ, Huang P, Shi R, Lee TH, Lu G, Zhang Z, Bronson R, Lu KP. The telomerase inhibitor PinX1 is a major haploinsufficient tumor suppressor essential for chromosome stability in mice. J Clin Invest 2011. PubMed
  • Soohoo CY, Shi R, Lee TH, Huang P, Lu KP, Zhou XZ. Telomerase inhibitor PinX1 provides a link between TRF1 and telomerase to prevent telomere elongation. J Biol Chem 2011; 286:3894-906. PubMed
  • Driver JA, Lu KP. Pin1: A New Genetic Link between Alzheimer's Disease, Cancer and Aging. 2010; 3:158-65. PubMed
  • Fan G,Fan Y,Gupta N,Matsuura I,Liu F,Zhou XZ,Lu KP,Gelinas C. Peptidyl-prolyl isomerase Pin1 markedly enhances the oncogenic activity of the rel proteins in the nuclear factor-kappaB family. Cancer Res 2009; 69:4589-97. PubMed
  • Ryo A,Wulf G,Lee TH,Lu KP. Pinning down HER2-ER crosstalk in SMRT regulation. Trends Biochem Sci 2009; 34:162-5. PubMed
  • Cole AR, Soutar MP, Rembutsu M, Van Aalten L, Hastie CJ, McLauchlan H, Peggie M, Balastik M, Lu KP, Sutherland C. Relative resistance of Cdk5-phosphorylated CRMP2 to dephosphorylation. J Biol Chem 2008; 283:18227-37. PubMed
  • Liao WL, Tsai HC, Wang HF, Chang J, Lu KM, Wu HL, Lee YC, Tsai TF, Takahashi H, Wagner M, Ghyselinck NB, Chambon P, Liu FC. Modular patterning of structure and function of the striatum by retinoid receptor signaling. Proc Natl Acad Sci U S A 2008; 105:6765-70. PubMed
  • Lu KH, Wu W, Dave B, Slomovitz BM, Burke TW, Munsell MF, Broaddus RR, Walker CL. Loss of tuberous sclerosis complex-2 function and activation of Mammalian target of rapamycin signaling in endometrial carcinoma. Clin Cancer Res 2008; 14:2543-50. PubMed
  • Lim J, Balastik M, Lee TH, Nakamura K, Liou YC, Sun A, Finn G, Pastorino L, Lee VM, Lu KP. Pin1 has opposite effects on wild-type and P301L tau stability and tauopathy. J Clin Invest 2008; 118:1877-1889. PubMed
  • Dehart WK, Gilliam AC, Lu KQ, Brell J. A rare case of melanoma recurring as subcutaneous metastatic melanoma with overlying ecchymoses. Arch Dermatol 2008; 144:561-2. PubMed
  • Lu HF, Chen YS, Yang JS, Chen JC, Lu KW, Chiu TH, Liu KC, Yeh CC, Chen GW, Lin HJ, Chung JG. Gypenosides induced G0/G1 arrest via inhibition of cyclin E and induction of apoptosis via activation of caspases-3 and -9 in human lung cancer A-549 cells. In Vivo 2008; 22:215-21. PubMed
  • Lam PB,Burga LN,Wu BP,Hofstatter EW,Lu KP,Wulf GM. Prolyl isomerase Pin1 is highly expressed in Her2-positive breast cancer and regulates erbB2 protein stability. Mol Cancer 2008; 7:91. PubMed
  • Lu KP, Finn G, Lee TH, Nicholson LK. Prolyl cis-trans isomerization as a molecular timer. Nat Chem Biol 2007; 3:619-29. PubMed
  • Wildemann D, Hernandez Alvarez B, Stoller G, Zhou XZ, Lu KP, Erdmann F, Ferrari D, Fischer G. An essential role for Pin1 in Xenopus laevis embryonic development revealed by specific inhibitors. Biol Chem 2007; 388:1103-11. PubMed
  • Li QM, Tep C, Yune TY, Zhou XZ, Uchida T, Lu KP, Yoon SO. Opposite regulation of oligodendrocyte apoptosis by JNK3 and Pin1 after spinal cord injury. J Neurosci 2007; 27:8395-404. PubMed
  • Balastik M, Lim J, Pastorino L, Lu KP. Pin1 in Alzheimer's disease: multiple substrates, one regulatory mechanism? Biochim Biophys Acta 2007; 1772:422-9. PubMed
  • Nicholson LK, Lu KP. Prolyl cis-trans Isomerization as a molecular timer in Crk signaling. Mol Cell 2007; 25:483-5. PubMed
  • Lu KP, Suizu F, Zhou XZ, Finn G, Lam P, Wulf G. Targeting carcinogenesis: a role for the prolyl isomerase Pin1? Mol Carcinog 2006; 45:397-402. PubMed
  • Pastorino L, Sun A, Lu PJ, Zhou XZ, Balastik M, Finn G, Wulf G, Lim J, Li SH, Li X, Xia W, Nicholson LK, Lu KP. The prolyl isomerase Pin1 regulates amyloid precursor protein processing and amyloid-beta production. Nature 2006; 440:528-34. PubMed
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