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ZHAO ZHizhuang

 

ZHAO Zhizhuang,PH.D.

Professor, Shool of Life Science, Jilin University

email:

Tel:+86-0431-

Fax:+86-0431-

Life Science Building, Jilin University, Qianjin Street No.2699,Changchun,P. R. China,

Postal Code:130012

Scientific research field description

Tyrosine Kinases and Phosphatases in Cell Signaling and in Diseases

       Tyrosine phosphorylation is a fundamental regulatory mechanism for numerous important aspects of human cellular physiology in health and disease.  This process is controlled by the coordinate action of tyrosine kinases (PTKs) and phosphatases (PTPs).  Activities of these enzymes are tightly regulated under normal conditions, and deregulation of the enzymes produces human diseases.  Our current research includes the following four areas.

       1. Tyrosine kinases and phosphatases in myeloproliferative neoplasms and other malignant diseases. We will focus on myeloproliferative neoplasms (MPNs), a group of hematologic malignancies characterized by excessive production of red blood cells, granulocytes, and/or platelets.  We have identified JAK2V617F, a gain-of-function mutant form of tyrosine kinase JAK2, in the majority of MPN patients.  By using a unique transgenic mouse model, we have demonstrated the pathogenicity of JAK2V617F.  We will further reveal how JAK2V617F alters the nature of hematopoietic stem cells thereby causing diseases.  We also intend to identify mutations of tyrosine kinases and phosphatases in other types of cancers including various solid tumors and leukemia.  Our ultimate goal is to study pathological functions of these mutant enzymes and to identify their inhibitors for therapeutic interventions.

       2.  Structure, regulation, and function of tyrosine phosphatases SHP-1 and SHP-2 and their regulatory proteins. SHP-1 and SHP-2 are two SH2 domain-containing tyrosine phosphatases with crucial roles in cell signaling and major pathological implications in human diseases including cancer and developmental disorders.  They are regulated by proteins containing the so-called immunoreceptor tyrosine-based inhibition motifs.  We have isolated two such proteins. One is PZR that specifically interacts with SHP-2 and the other is LAIR-1 that only binds to SHP-1. These proteins represent major anchor proteins of SHP-1 and SHP-2 on the cell surface, and we believe that they are key upstream regulators of the enzymes. By using various tools including antibodies, purified proteins, retroviral cDNA constructs, and transgenic/knockout mice, we will define at the molecular and cellular levels how LAIR-1 and PZR regulate the activity of SHP-1 and SHP-2 thereby controlling cell growth and mobility.

       3. Tyrosine phosphatases in diabetes and obesity.  PTPs have a major role in development of metabolic diseases.  For example, mice deficient in PTP1B display hypersensitivity to insulin and resistance to high-fat diet-induced obesity.  This makes PTP1B an excellent target for therapeutic drug development.  Our goal is to indentify inhibitors of PTP1B form natural products as well as chemical libraries and further to verify the effectiveness of these inhibitors in treatment and prevention of diabetes and obesity.

       4. Structure, regulation, and function of MTM subfamily tyrosine phosphatases.  MTMs represent a subfamily of PTPs that preferably dephosphorylate phosphatidylinositol 3-phosphate, a second messenger with crucial function in membrane trafficking and cell signaling. We have identified several such enzymes in humans and in C. elegans.  By using RNAi-mediated gene knockdown, we found a crucial role of these enzymes in mobility, muscle maintenance, and aging of the C. elegans worms.  We will further characterize the functions of these enzymes in membrane trafficking and cell signaling and their implications for human diseases including sarcopenia.

Representative papers

1、Runxiang Zhao, Shu Xing, Zhe Li, Xueqi Fu, Qingshan Li, Sanford B. Krantz, Z. Joe Zhao. Identification of an Acquired JAK2 Mutation in Polycythemia Vera. J. Biol. Chem. 280, 22788-22792 (2005).

2、Xuesong Xu, Qi Zhang, Jian Luo, Shu Xing, Qingshan Li, Sanford B. Krantz, Xueqi Fu, Zhizhuang Joe Zhao.  JAK2V617F:  Prevalence in a Large Chinese Hospital Population.  Blood.  109, 339-342. (2007)

3、Zhe Li, Mingjiang Xu, Shu Xing, Wanting Tina Ho, Takefumi Ishii, Qingshan Li, Xueqi Fu,  Zhizhuang Joe Zhao. Erlotinib Effectively Inhibits JAK2V617F Activity and Polycythemia Vera Cell Growth.  J Biol Chem.  282(6):3428-32.  (2007).

4、Junfeng Ma, Fenghua Zeng, Wanting Ho, Lirong Teng, Qingshan Li, Xueqi Fu, Zhizhuang Joe Zhao.  Characterization and Functional Studies of a FYVE Domain-Containing Phosphatase in C. elegans.  J. Cellular. Biochem.  2008;104:1843-52. PMID: 18393358.

5、Shu Xing, Wanting Tina Ho, Wanming Zhao, Junfeng Ma, Shaofeng Wang, Xuesong Xu, Qingshan Li, Xueqi Fu, Mingjiang Xu, Zhizhuang Joe Zhao. Transgenic Expression of JAK2V617F Causes Myeloproliferative Disorders in Mice.  Blood.  2008;111 5109-5117. PMID: 18334677. 

6、Wanming Zhao, Rufei Gao, Jiyun Lee, Shu Xing, Wanting T Ho, Xueqi Fu, Shibo L, Zhizhuang Joe Zhao. Relevance of JAK2V617F positivity to hematological diseases - survey of samples from a clinical genetics laboratory.  J. Hematol. Oncol.  2011 Jan 14;4(1):4. PMCID: PMC3032761

7、Junfeng Ma, Zhe Li, Shu Xing, Wanting T Ho, Xueqi Fu, Zhizhuang Joe Zhao. Tea contains potent inhibitors of tyrosine phosphatase PTP1B. Biochem. Biophys. Res. Commun.  2011 Apr 1;407(1):98-102. Epub 2011 Feb 28.

8、Xiaokun Yu; Wanming Zhao; Junfeng Ma; Xueqi Fu; Zhizhuang Joe Zhao. Beneficial and Harmful Effects of Alcohol Exposure on Caenorhabditis elegans Worms. Biochem. Biophys. Res. Commun.  2011 Sep 9;412(4):757-62. Epub 2011 Aug 17. PMID: 21871869

9、Anna H. Zhao, Rufei Gao, and Zhizhuang Joe Zhao. Development of a highly sensitive method for detection of JAK2V617F. J Hematol Oncol. 2011 Oct 10;4:40. PMID: 21985400

10、Gao R, Zhao AH, Du Y, Ho WT, Fu X, Zhao ZJ. PCR artifacts can explain the reported biallelic JAK2 mutations. Blood Cancer J. 2012 Feb;2(2):e56. PMID:22829246.

11、Zhao W, Du Y, Ho WT, Fu X, Zhao ZJ. JAK2V617F and p53 mutations coexist in erythroleukemia and megakaryoblastic leukemic cell lines. Exp Hematol Oncol. 2012 Jun 21;1(1):15. PMID:23210734. PMCID:PMC3514099

12、Yu X, Ma J, Lin F, Zhao W, Fu X, Zhao ZJ. Myotubularin family phosphatase ceMTM3 is required for muscle maintenance by preventing excessive autophagy in Caenorhabditis elegans. BMC Cell Biol. 2012 Oct 31;13:28. PMID:23114011.

13、Guo Y, Chen Y, Xu X, Fu X, Zhao ZJ. SU11652 Inhibits tyrosine kinase activity of FLT3 and growth of MV-4-11 cells. J Hematol Oncol. 2012 Dec 6;5(1):72. PMID:23216927

14、Hassed SJ, Wiley GB, Wang S, Lee JY, Li S, Xu W, Zhao ZJ, Mulvihill JJ, Robertson J, Warner J, Gaffney PM. RBPJ mutations identified in two families affected by Adams-Oliver syndrome. Am J Hum Genet. 2012 Aug 10;91(2):391-5. PMID:22883147

15、Andrew Chow, Matthew Huggins, Jalal Ahmed, Daigo Hashimoto, Daniel Lucas, Yuya Kunisaki, Sandra Pinho, Marylene Leboeuf, Clara Noizat, Nico van Rooijen, Masato Tanaka, Zhizhuang Joe Zhao, Aviv Bergman, Miriam Merad & Paul S Frenette.  CD169+ macrophages provide a niche promoting erythropoiesis under homeostasis and stress.  Nature Medicine.  2013 Apr;19(4):429-36. PMID:23502962

16、Jian Zhong Tang, Catherine Carmichael, Wei Shi, Donald Metcalf, Ashley P. Ng, Craig D. Hyland, Nancy A. Jenkins, Neal G. Copeland, Viive M. Howell, Zhizhuang Joe Zhao, Gordon K. Smyth, Benjamin T. Kile, Warren S. Alexander.  Transposon mutagenesis reveals cooperation of ETS family transcription factors with signaling pathways in erythro-megakaryocytic leukemia. Proc Natl Acad Sci U S A. 2013 Apr 9;110(15):6091-6. PMCID:PMC3625293

College of Life Sciences, Jilin University,Changchun,China,130012

Tel:+86-431-81969061  Email: smxyld@jlu.edu.cn