Ke Shuai, Ph.D.

Mailing Address:
11-934 Factor Bldg.
CAMPUS - 167817
CA

Work Address:
Factor
Los Angeles, CA 90095 Factor
Los Angeles, CA 90095

Affiliations
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
Research Interests
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.
Publications

A selected list of publications:

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.