Affiliations

Professor, Hematology-Oncology, Biological Chemistry

Member, Gene Regulation GPB Home Area, Immunity, Microbes & Molecular Pathogenesis GPB Home Area, JCCC Signal Transduction and Therapeutics Program Area

Cell growth, differentiation, survival, and apoptosis can be regulated by cytokines, growth factors, and cellular stresses that trigger distinct as well as overlapping signaling pathways. The overall research interest in Dr. Ke Shuai’s laboratory is to study the molecular mechanisms of cell signaling, and how altered signaling events contribute to the development of human diseases such as cancers and immune disorders. Our work is currently focused on understanding the role of the PIAS (protein inhibitor of activated STAT) protein family in the regulation of various cellular responses. PIAS proteins were originally identified in our laboratory as negative regulators of STATs (signal transducer and activator of transcription). PIAS proteins possess SUMO (small ubiquitin-related modifier) E3 ligase activity that function to promote the sumoylation of various protein molecules involved in gene regulation. We are interested in studying the molecular mechanisms, the regulation, and the biological roles of PIAS proteins in cellular signaling using a combined biochemical and genetic approach. Our most recent studies indicate that PIAS1 is recruited to chromatin upon stimulation by a variety of signals, including cytokines, growth factors and TCR activation. The binding of PIAS1 to chromatin promotes the formation of a repressive chromatin state, resulting in the epigenetic silencing of PIAS1-target genes. PIAS1 acts by recruiting chromatin modification enzymes including DNA methyl transferases (DNMTs) and HP1 to gene promoters. The importance of this newly identified PIAS1 epigenetic regulatory pathway is being actively investigated in our laboratory.

Liu Bin, Yee Kathleen M, Tahk Samuel, Mackie Ryan, Hsu Cary, Shuai Ke PIAS1 SUMO ligase regulates the self-renewal and differentiation of hematopoietic stem cells. The EMBO journal. 2014; 33(2): 101-13. Liu Bin, Tahk Samuel, Yee Kathleen M, Yang Randy, Yang Yonghui, Mackie Ryan, Hsu Cary, Chernishof Vasili, O'Brien Neil, Jin Yusheng, Fan Guoping, Lane Timothy F, Rao Jianyu, Slamon Dennis, Shuai Ke PIAS1 regulates breast tumorigenesis through selective epigenetic gene silencing. PloS one. 2014; 9(2): e89464. Schindler Chris, Shuai Ke, Prezioso Vincent R, Darnell James E Pillars article: Interferon-dependent tyrosine phosphorylation of a latent cytoplasmic transcription factor. Science. 1992. 257: 809-813. Journal of immunology (Baltimore, Md. : 1950). 2011; 187(11): 5489-94. Liu Bin, Tahk Samuel, Yee Kathleen M, Fan Guoping, Shuai Ke The ligase PIAS1 restricts natural regulatory T cell differentiation by epigenetic repression. Science (New York, N.Y.). 2010; 330(6003): 521-5. Liu Bin, Shuai Ke Summon SUMO to wrestle with inflammation. Molecular cell. 2009; 35(6): 731-2. Liu Bin, Shuai Ke Regulation of the sumoylation system in gene expression. Current opinion in cell biology. 2008; 20(3): 288-93. Dawlaty Meelad M, Malureanu Liviu, Jeganathan Karthik B, Kao Esther, Sustmann Claudio, Tahk Samuel, Shuai Ke, Grosschedl Rudolf, van Deursen Jan M Resolution of sister centromeres requires RanBP2-mediated SUMOylation of topoisomerase IIalpha. Cell. 2008; 133(1): 103-15. Liu Bin, Shuai Ke Targeting the PIAS1 SUMO ligase pathway to control inflammation. Trends in pharmacological sciences. 2008; 29(10): 505-9. Tahk, S Liu, B Chernishof, V Wong, KA Wu, H Shuai, K Control of specificity and magnitude of NF-kappaB and STAT1-mediated gene activation through PIASy and PIAS1 cooperation. Proceedings of the National Academy of Sciences of the United States of America. 2007; 104(28): 11643-8. Shalizi A. Bilimoria P.M. Stegmuller J. Gaudilliere B. Yang Y. Shuai K. Bonni A. PIASx is a MEF2 SUMO E3 ligase that promotes postsynaptic dendritic morphogenesis. J Neurosci 2007; 27: 10037-46. Liu B, Yang Y, Chernishof V, Ogorzalek-Loo R, Jang H, Tahk S, Yang R, Mink S, Schultz D, Bellone C, Loo J, Shuai K Pro-Inflammatory stimuli induce IKKa-mediated Phosophorylation of PIAS1 to restrict inflammation and immunity. Cell 2007; 129: 903-904. Dadke S, Cotteret S, Yip SC, Jaffer Z, Haj F, Ivanov A, Rauscher F, Shuai K, Ng T, Neel B, Chernoff J Regulation of Protein Tyrosine Phosphatase (PTP) 1B by sumoylation. Nat. Cell Biol 2007; 9: 80-85. Shuai K Regulation of cytokine signaling pathways by PIAS proteins. Cell Res 2006; 16: 196-202. Malakhova, OA Kim, KI Luo, JK Zou, W Kumar, KG Fuchs, SY Shuai, K Zhang, DE UBP43 is a novel regulator of interferon signaling independent of its ISG15 isopeptidase activity. The EMBO journal. 2006; 25(11): 2358-67. Fan G, Martinowich MH, Chin F, He SD, Fouse L, Hutnick D, Hattori W, Ge Y, Shen H, Wu J, ten Hoeve J, Shuai K, Sun YE DNA Methylation controls the timing of astrogliogenesis through regulation of JAK-STAT signaling. Development 2005; 132: 3345-3356. Henriksen MA, Zhong M, Takeuchi K, Schafer O, Bouman L, ten Hoeve J, Ren S, Chen X, Shuai K*, Darnell JE* (*co-corresponding authors) Implications of an anti-parallel dimeric structure of nonphosphorylated STAT1 for the activation-inactivation cycle. Proc. Natl. Acad. Sci 2005; 102: 3966-3971. Zhong M, Henriksen MA, Takeuchi K, Schaefer O, Liu B, ten Hoeve J, Ren Z, Mao X, Chen X, Shuai K, Darnell JE Implications of an antiparallel dimeric structure of nonphosphorylated STAT1 for the activation-inactivation cycle. Proceedings of the National Academy of Sciences of the United States of America. . 2005; 102(11): 3966-71. Liu B, Yang R, Wong KA, Getman C, Stein N, Teitell MA, Cheng G, Wu H, Shuai K Negative regulation of NF-kappaB signaling by PIAS1. Molecular and cellular biology. . 2005; 25(3): 1113-23. Shuai K, Liu B Regulation of gene-activation pathways by PIAS proteins in the immune system. Nat. Rev. Immunol 2005; 5: 593-605. Liu B, Mink S, Wong KA, Stein N, Getman C, Dempsey PW, Wu H, Shuai K PIAS1 selectively inhibits interferon-inducible genes and is important in innate immunity. Nature immunology. . 2004; 5(9): 891-8. Gross M, Yang R, Top I, Gasper C, Shuai K PIASy-mediated repression of the androgen receptor is independent of sumoylation. Oncogene. . 2004; 23(17): 3059-66. Arora T, Liu B, He H, Kim J, Murphy TL, Murphy KM, Modlin RL, Shuai K PIASx is a transcriptional co-repressor of signal transducer and activator of transcription 4. The Journal of biological chemistry. . 2003; 278(24): 21327-30. Malakhova OA, Yan M, Malakhov MP, Yuan Y, Ritchie KJ, Kim KI, Peterson LF, Shuai K, Zhang DE Protein ISGylation modulates the JAK-STAT signaling pathway. Genes & development. . 2003; 17(4): 455-60. Shuai K, Liu B Regulation of JAK-STAT signalling in the immune system. Nature reviews. Immunology. . 2003; 3(11): 900-11. Long J, Matsuura I, He D, Wang G, Shuai K, Liu F Repression of Smad transcriptional activity by PIASy. Proc. Natl. Acad. of Sci 2003; 100: 9791-9796. Shuai K Serine phosphorylation: arming Stat1 against infection. Immunity. . 2003; 19(6): 771-2. ten Hoeve J, Ibarra-Sanchez MJ, Yu Y, Zhu W, Tremblay M, David M, Shuai K Identification of a nuclear Stat1 protein tyrosine phosphatase. Mol. Cell. Biol 2002; 22: 5662-5668. Kim J, Uyemura K, Van Dyke MK, Legaspi AJ, Rea TH, Shuai K, Modlin RL A role for IL-12 receptor expression and signal transduction in host defense in leprosy. Journal of immunology (Baltimore, Md. : 1950) . 2001; 167(2): 779-86. Liu B, Gross M, ten Hoeve J, Shuai K A transcriptional corepressor of Stat1 with an essential LXXLL signature motif. Proceedings of the National Academy of Sciences of the United States of America. . 2001; 98(6): 3203-7. Mowen KA, Tang J, Zhu W, Schurter BT, Shuai K, Herschman HR, David M Arginine methylation of STAT1 modulates IFNa/b-induced transcription. Cell 2001; 104: 731-741. Gross M, Liu B, Tan J, French FS, Carey M, Shuai K Distinct effects of PIAS proteins on androgen-mediated gene activation in prostate cancer cells. Oncogene. . 2001; 20(29): 3880-7. Liu B, Shuai K Indiction of apoptosis by protein inhibitor of activated Stat 1 through c-Jun NH2-terminal kinase activation. J. Biol. Chem 2001; 276: 36624-36631. Liao J, Fu Y, Shuai K Distinct roles of the NH2-terminal and COOH-terminal domains of PIAS1 in cytokine-induced PIAS1-Stat1 interaction. Proc. Natl. Acad. Sci 2000; 97: 5267-5272. Shuai K Modulation of STAT signaling by STAT-interacting proteins. Oncogene. . 2000; 19(21): 2638-44. Tan J, Hall SH, Hamil KG, Grossman G, Petrusz P, Liao J, Shuai K, French FS Protein inhibitor of activated STAT-1 (signal transducer and activator of transcription-1) is a nuclear receptor coregulator expressed in human testis. Molecular endocrinology (Baltimore, Md.) . 2000; 14(1): 14-26. Graeber TG, Shuai K Rapid gene repression triggered by interlukin-6 at the onset of monocyte differentiation. Biochem. Biophsy. Res. Commun 2000; 267: 863-869. Roedel B, Tavassoli K, Karsunky H, Schmidt T, Bachmann M, Schaper F, Heinrich P, Shuai K, Elsaesser HP, Moeroey T The zinc finger protein Gfi-1 can enhance STAT3 signaling by interacting with the STAT3 inhibitor PIAS3. EMBO J 2000; 19: 5845-5855. Shuai K The STAT family of proteins in cytokine signaling. Prog. Biophys. Mol. Biol 1999; 71: 405-422. Garcia VE, Jullien D, Song M, Uyemura K, Shuai K, Morita CT, Modlin RL IL-15 enhances the response of human gamma/delta T cells to nonpeptide microbial antigens. J. Immunology 1998; 160: 4322-4329. Liu B, Liao J, Rao X, Kushner SA, Chung CD, Chang DD, Shuai K Inhibition of Stat1-mediated gene activation by PIAS1. Proceedings of the National Academy of Sciences of the United States of America. . 1998; 95(18): 10626-31. Mark M Song, Ke Shuai The Suppressor of Cytokine Signaling (SOCS) 1 and SOCS3 but Not SOCS2 Proteins Inhibit Interferon-mediated Antiviral and Antiproliferative Activities. J. Biol. Chem 1998; 273: 35056-35062. Chung CD, Liao J, Liu B, Rao X, Jay P, Berta P, Shuai K Specific inhibition of Stat3 signal transduction by PIAS3. Science. . 1997; 278(5344): 1803-5. Shuai K, Halpern J, ten Hoeve J, Rao X, Sawyers CL Constitutive activation of STAT5 by the BCR-ABL oncogene in chronic myelogenous leukemia. Oncogene. . 1996; 13(2): 247-54. Shuai K, Liao J, Song MM Enhancement of antiproliferative activity of gamma interferon by the specific inhibition of tyrosine dephosphorylation of Stat1. Molecular and cellular biology. . 1996; 16(9): 4932-41. Shuai K, Horvath CM, Huang LH, Qureshi SA, Cowburn D, Darnell JE Interferon activation of the transcription factor Stat91 involves dimerization through SH2-phosphotyrosyl peptide interactions. Cell. . 1994; 76(5): 821-8. Sadowski HB, Shuai K, Darnell JE jr, Gilman MZ A Common Nuclear Signal Transduction Pathway Activated by Growth Factor and Cytokine Receptors. Science 1993; 261: 1739-44. Shuai K, Stark GR, Kerr IM, Darnell JE A single phosphotyrosine residue of Stat91 required for gene activation by interferon-gamma. Science. . 1993; 261(5129): 1744-6. Shuai K, Ziemiecki A, Wilks AF, Harpur AG, Sadowski HB, Gilman MZ, Darnell JE Jr Polypeptide Signaling to the Nucleus through Tyrosine Phosphorylation of Jak and Stat Proteins. Nature 1993; 366: 580-3. Shuai K, Schindler C, Prezioso VR, Darnell JE Activation of transcription by IFN-gamma: tyrosine phosphorylation of a 91-kD DNA binding protein. Science. . 1992; 258(5089): 1808-12. Schindler C, Shuai K, Prezioso VR, Darnell JE Interferon-dependent tyrosine phosphorylation of a latent cytoplasmic transcription factor. Science. . 1992; 257(5071): 809-13.