Department / Division Affiliations
Professor,
Hematology-Oncology,
Biological Chemistry
Member,
ACCESS Program: Dept. of Biological Chemistry,
JCCC Signal Transduction and Therapeutics Program Area
Research Interest:
Signal Transduction and Gene Expression
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. Abnormal signaling is associated with human cancer. The overall research interest in my laboratory is to study cellular signal transduction pathways in normal and tumor cells. These studies may provide novel therapeutic targets for cancer treatment.
Our work is currently centered in two areas: 1) To study the role of PIAS (protein inhibitor of activated STAT) proteins in cellular signaling. In studies aimed at the understanding of cytokine-activated JAK-STAT signaling pathway, our laboratory has discovered the PIAS family of proteins, which can inhibit the activity of STATs. In addition, PIAS proteins have also been shown to possess SUMO (small ubiquitin-related modifier) E3 ligase activity and can regulate a number of other transcription factors, including p53 and androgen receptor. We are studying the molecular mechanism, the regulation, and the biological roles of PIAS proteins in cellular signaling using a combined biochemical and genetic approach. 2) To study the regulation of the JAK-STAT signaling pathway. Cytokines bind to their cell surface receptors to activate signal transduction pathways that regulate numerous fundamental cellular processes, including cell growth and differentiation, immune and inflammatory responses. The JAK-STAT pathway is widely utilized by many cytokines and is regulated at multiple steps. The study on the regulation of the JAK-STAT pathway is important since abnormal JAK-STAT signaling is associated with immune diseases and cancers. Our laboratory is studying several regulatory mechanisms in the JAK-STAT pathway, including the dephosphorylation of STATs by protein tyrosine phosphatases and the regulation of the JAK-STAT pathway upon viral infection.
Publications:
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.
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.
Shuai K, Liu B Regulation of gene-activation pathways by PIAS proteins in the immune system.
Nat. Rev. Immunol.
2005; 5:
593-605.
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.
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.
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.
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.
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.
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.
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, 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.
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.
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.
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.
Shuai K Serine phosphorylation: arming Stat1 against infection..
Immunity. .
2003; 19(6):
771-2.
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.
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.
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.
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.
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, 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, 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, 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.
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, 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.
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