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Zheng Lab

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Yi Zheng, PhD is a faculty member in the Division of Experimental Hematology at Cincinnati Children's Hospital Medical Center.

Yi Zheng, PhD

Title

Director, Division of Experimental Hematology and Cancer Biology; Katherine Stewart Waters Endowed Chair

Appointment

Professor of Pediatrics, University of Cincinnati College of Medicine

Email

yi.zheng@chmcc.org

Phone

513-636-0595

Fax

513-636-3768

Credentials

PhD: Cornell University, Ithaca, NY, 1991

Postdoctoral Fellow: Cornell University, Ithaca, NY, 1995

Position History

Professor and Director, Cell Signaling Program, Division of Experimental Hematology, Children's Hospital Research Foundation, University of Cincinnati, Ohio (3/02 - present)

Professor, Department of Molecular Sciences
College of Medicine, University of Tennessee Health Science Center, Memphis, TN (7/01 - 2/02)

Associate Professor, Department of Molecular Sciences
College of Medicine, University of Tennessee Health Science Center, Memphis, TN (10/00 - 6/01)

Associate Professor, Department of Biochemistry
College of Medicine, University of Tennessee, Memphis, TN (7/98 - 9/00)

Assistant Professor, Department of Biochemistry,
College of Medicine, University of Tennessee, Memphis, TN (9/95 - 6/98)

Awards and Honors

  • Katherine Stewart Waters Endowed Chair, Cincinnati Children's Research Foundation (2006).
  • Tennessee Science Alliance Faculty Awards (2001).
  • Outstanding oversea's young scholar award, Chinese National Science Foundation (1998).
  • Wentink Outstanding Graduate Student Award, Department of Chemistry, Cornell University (1991).
  • Cornell Biotechnology Fellow, Cornell University (1988-1991).

Research

Connect to Yi Zheng's laboratory webpage

The Rho family small GTP-binding proteins of Ras superfamily, including Rho, Rac, and Cdc42, are a class of intracellular signal transducers that play important roles in the regulation of cell growth and actin-based morphogenesis. Like Ras, mutation, overexpression or disruption of the normal mode of regulation of these GTP-binding and GTP-hydrolyzing molecular switches may lead to growth transformation, morphological alteration and developmental disorder. Work in the laboratory seeks to understand the molecular mechanisms of various signal transduction processes involving Rho GTPases, their regulators, and effector targets. The emphasis is on defining their physiological roles using gene targeted mouse models and delineating their pathological roles in human diseases. The ultimate goals are to develop novel therapeutic reagents that may interfere with specific Rho pathways related to human pathological conditions, cancer in particular.

The ongoing research projects in the Zheng laboratory include:

  1. Using transgenic and gene targeted mouse models to study the physiological roles of Rho GTPases and their regulators in hematopoiesis and brain development. We are focusing on characterization of the RhoA, Cdc42 and Rac1 conditional knockout mice to define the unique, essential roles of these small GTPases in hematopoietic stem cells and neural stem cells.
  2. Investigation of the functional interaction between Rho GTPases and the p53 tumor suppressor pathway. The goals are to dissect the molecular pathways of Rho GTPases that cooperate with p53 deficiency in promoting cell transformation and invasion and to implicate individual members of the Rho family as anti-cancer targets in the p53 deficient onco-mouse model. One specific area of interests is to study the involvement of individual Rho GTPases in cancer stem cell regulation, particularly the contribution to maintaining cancer stem cell interaction with the microenvironment, "niche".
  3. Mechanism based, rationalized small molecule inhibitor design to target specific Rho GTPase functions. The hope is that the selected compounds could be explored as novel therapeutic reagents acting on specific Rho GTPase mediated signaling pathways that might reverse cancer stem cell phenotypes or modulate normal stem cell functions for therapeutic applications.
  4. Elucidation of the mechanisms underlying the molecular interactions between individual Rho family GTPases and their regulatory/effector proteins, with goals to gain insight to the mechanisms of regulation of the Rho proteins and to address the issue how the signals bifurcate at the small GTP-binding proteins to cause diverse cellular responses.
  5. Structure-function studies of Rho GTPase-activating proteins (GAPs) and the Dbl-family guanine nucleotide exchange factors (GEFs), with goals to understand the mechanism of regulation and signaling pathways of RhoGAPs/GEFs and to determine the cellular functions of these putative negative regulators or activators of Rho GTPases in relationship to tumorigenesis or hematopoiesis.

Research Grants and Contracts

 NIH R01 GM53943 (PI: Yi Zheng)
National Institute of General Medical Sciences  04/01/1996 - 03/31/2010
"Studies of Dbl-like regulators of small GTP-binding proteins"
The goals are to understand the structure-function relationship of two Dbl-like GEFs, LARG and Clg, and to determine the mechanisms of signal transduction involving these Dbl-like molecules.


NIH R01 CA141341 (PI: Yi Zheng)
National Cancer Institute      01/01/2000 - 01/31/2014
"Rac GTPase specific small molecule inhibitors"
The goals are to characterize lead inhibitors of Rac GTPase signaling and to apply them for leukemia stem cell eradication. 

1R01CA150547-01 (dual PI: Yi Zheng (contact), James Mulloy)
National Cancer Institute 04/01/2010 – 03/31/2015
“Targeting Cdc42 in leukemia stem cells”
The goals are to genetically implicate the Rho GTPase Cdc42 as a validate target in leukemia stem cells and to apply a lead small molecule inhibitor of Cdc42 for therapeutic benefits. 

NIH R01 CA125658 (PI: Yi Zheng)
National Cancer Institute 02/01/2007 – 01/31/2012
“Rac GTPases as Targets in Lymphomagenesis”
The goals are to implicate the functional connection between the p53 tumor suppressor and Rac GTPase signaling pathways in p53 deficient mouse and human lymphoma models and to validate Rac signaling as a useful anti-cancer target.

NIH R01 CA125658 S1 (PI: Yi Zheng)
National Cancer Institute 09/30/2009 – 09/29/2011
“Rac GTPases as Targets in Lymphomagenesis”
The goal is to design, identify and validate Rac GTPase specific small molecule inhibitors.

NIH R01 NS056435 (PI: Chia-Yi Kuan, Co-PI Yi Zheng) 
National Institute of Neurological Disorder and Stroke   07/01/2008 – 06/30/2012 
“Rac GTPases in mammalian brain development”
The goals are to define the role of Rac GTPases in neuronal regulation during forebrain development using mouse models. 

NIH T32 HL091805 (PI: Yi Zheng) 
National Institute of Heart, Lung, and Blood   09/01/2008 – 08/31/2013
“Training Program in Hematologic and Oncologic Diseases”
This is an institutional pre-doctoral and post-doctoral training program aimed at educating and training the next generation of academic researchers, educators, and physician scientists in H/O diseases.

Publications, Most Recent

Connect to Yi Zheng's publications on PubMed

Maillet M, Lynch JM, Sanna B, York AJ, Zheng Y, Molkentin JD. (2009) Cdc42 is an antihypertrophic molecular switch in the mouse heart.  J Clin Invest. 119(10):3079-88.

James C. Mulloy, Jose A. Cancelas, Marie-Dominique Filippi, Theodosia A. Kalfa, Fukun Guo, and Yi Zheng. Rho GTPases in hematopoiesis and hemopathies.  Blood in press.

Xu, H., Geiger, H., Szczer, K., Deira, D., Zheng, Y., Settleman, J., Williams, D. A., and Filippi, M.-D. (2009) Loss of the Rho GTPase activating protein p190-B enhances hematopoietic stem cell engraftment potential.  Blood. 2009 Oct 22;114(17):3557-66

Szczur, K., Zheng, Y., and Filippi, M.-D. (2009) The Rho GTPase Cdc42 regulates neutrophil polarity via microtubule driven CD11b integrin signaling.  Blood. 2009 Sep 14. [Epub ahead of print]

Milsom, M. D., Lee, A. W., Zheng, Y., Cancelas, J. A.  (2009) Fanca-/- hematopoietic stem cells demonstrate a mobilization defect which can be overcome by administration of the Rac inhibitor NSC23766. Haematologica  94(7):1011-5.

Stengel, K. R., Chellapangal, T., Solomon, D. A., Angus, S. P., Zheng, Y., Knudsen, E. S. (2009) RB/p107/130 pocket proteins: Protein dynamics and interactions with target gene promoters.  J. Biol. Chem. 284(29):19265-71.

Kalfa, T. A., Pushkaran, S., Cancelas, J. A., Johnson, J. F., Daria, D., Geiger, H., Williams, D. A., and Zheng, Y.  (2009) Rac GTPases Regulate Early Erythropoietic Differentiation.  Haematologica in press.

Xu, C., Zhang, Y. H., Thangavel, M., Richardson, M. M., Liu, L., Zhou, B., Zheng, Y., Ostrom, R. S., and Zhang, X. A. (2009) CD82 endocytosis and cholesterol-dependent reorganization of tetraspanin webs and lipid rafts.  FASEB J. FASEB J. 2009 Oct;23(10):3273-88

Guo F, Velu CS, Grimes HL, and Zheng, Y. (2009) Rho GTPase Cdc42 is essential for B lymphocyte development and activation.  Blood 114(14):2909-16.

Marchioni, F., and Zheng, Y. (2008) Targeting Rho GTPases by peptidic structures.Curr Pharm Des. 2009;15(21):2481-7.

Bosco, E., Mulloy, J., and Zheng, Y. (2008) Rac1 GTPase: a “Rack” of all trade.  Cell Mol Life Sci. 2009 Feb;66(3):370-4.

Zhang, S., Tang, Q., Deng, Y., Xue, Y., Liu, M., Liu, S., Xu, F., Shi, F., Zheng, Y., Bi, F. (2008) RhoA regulates G1/S progression of gastric cancer cells by modulation of multiple INK4 family tumor suppressors. Mol Cancer Res. 2009 Apr;7(4):570-80.

Flevaris, P., , Li, Z., Zhang, G., Zheng, Y., Liu, J., and Du, X.  Two distinct roles of mitogen-activated protein kinases in platelets and a novel Rac1-MAPK-dependent integrin outside-in retractile signaling pathway.Blood. 2009 Jan 22;113(4):893-901.

Mulloy, J., Wunderlich, M., Zheng, Y., and Wei, J. (2008) Transforming Human Blood Stem and Progenitor Cells: A New Way Forward in Leukemia Modeling.Cell Cycle 2008 Nov. 8, PMID: 18948748.

Grogg, M., and Zheng, Y. (2008) Rho GTPase-activating proteins in cancer. Springer Publisher, in press.

Guo, F., Cancelas, J., Hilderman, D., Williams, D. A., and Zheng, Y. (2008) Rac GTPase isoforms, Rac1 and Rac2, play redundant and critical role in T-cell development.Blood 112(5):1767-75.

Kalfa, T. A., Pushkaran, S., Cancelas, J. A., Johnson, J. F., Daria, D., Geiger, H., Williams, D. A., and Zheng, Y. (2008) Rac GTPases Regulate Early Erythropoietic Differentiation and Red Blood Cell Enucleation. Submitted.

Chen, L., Melendez, J., Campbell, K., Kuan, C.-Y., and Zheng, Y. (2008) Rac1 deficiency in the forebrain results in neural progenitor reduction and microcephaly.Dev. Biol. 2008 Oct. 31, PMID: 19007770.

Tan, W., Palmby, T. R., Gavard, J., Amornphimoltham, P., Zheng, Y., Gutkind, J. S. (2008) Rac1 is essential for vascular development.FASEB J. 22(6):1829-38.

Thomas, E. K., Cancelas, J. A., Zheng, Y., and Williams, D. A. (2008) Rac GTPases as key regulators of p210-BCR-ABL-dependent leukemogenesis.Leukemia 22(5):898-904.

Williams, D. A., Zheng, Y., and Jose A. Cancelas, J. A. (2008) Rho GTPases and the regulation of hematopoietic stem cell localization.Methods in Enzymology 439:365-93.

Müller, L.U.W., Schore, R. J., Zheng, Y., Thomas, E. K., Kim, M.-O., Cancelas, J. A., Gu, Y., and Williams, D. A. (2008) Rac Guanosine Triphosphatases represent a potential target in AML.Leukemia 22(9):1803-6.

Zhang, X., Shang, X., Guo, F., Murphy, K., Kirby, M., Kelly, P., Reeves, L., Smith, F. O., Williams, D. A., Zheng, Y.*, and Pang, Q.* (2008) Defective adhesion, migration and homing are associated with altered Cdc42 activity in cells from Fanconi anemia patients.Blood 112(5):1683-6. *co-senior authors.

Wei, J., Fox, C., Wunderlich, M., Alvarez, S., Cigudosa, J. C., Wilhelm, J. E., Zheng, Y., Cancelas, J., Gu, Y., Jansen, M., DiMartino, J. F., and Mulloy. J. C. (2008) Microenvironment Determines Lineage Fate in a Human Model of MLL-AF9 Leukemia.Cancer Cell 13, 483-495.

Chan, A, Akhtar, M, Brenner, M, Zheng, Y, Gulko, PS, and Symons, M. (2007) The small GTPase Rac1 regulates the proliferation and invasion of fibroblast-like synoviocytes from rheumatoid arthritic patients.Mol Med. 13(5-6):297-304.

Yang, L, Wang, L, Kalfa, T, Cancelas, JA, Shang, X, Pushkaran, S, Mo, J, Williams, DA, Zheng, Y. (2007) Cdc42 critically regulates the balance between myelopoiesis and erythropoiesis.Blood 110: 3853 - 3861.

Liu, N., Zhang, G., Bi, F., Pan, Y., Xue, Y., Shi, Y., Zheng, Y., and Fan, D. (2007) RhoC is essential for gastric cancer metastasis. J. Mol. Medicine 85(10):1149-1156.

Vanni C, Mancini P, Ottaviano C, Ognibene M, Parodi A, Merello E, Russo C, Varesio L, Zheng Y, Torrisi MR, Eva A (2007) Ga13 regulation of proto-Dbl signaling.Cell Cycle 6(16):2058-70.

Thomas, E. K., Cancelas, J. A., Chae, H.-D., Cox, A. D., Keller, P. J., Danilo Perrotti, Neviani, P., Druker, B. J., Setchell, K. D. R., Zheng, Y., Harris, C. E., and Williams, D. A. (2007) Rac guanosine triphosphatases represent integrating molecular therapeutic targets for BCR-ABL-induced myeloproliferative disease.Cancer Cell 12, 467-478.

Yang, L., and Zheng, Y. (2007) Cdc42 – a signal coordinator in hematopoietic stem cell maintenance.Cell Cycle 6, 1445 - 1450.

Akbar, H, Kim, J, Funk, K, Cancelas, JA, Shang, X, Chen, L, Johnson, JF, Williams, DA, Zheng Y. (2007)  Genetic and pharmacological evidence that Rac1 GTPase is involved in regulation of platelet secretion and aggregation. J Thromb Haemost. 5(8):1747-1755.

Chen, L., Liao, G., Walclaw, R., Burns, K. A., Linquist, D., Campbell, K., Zheng, Y.*, and Kuan, C.-Y.* (2007) Rac1 controls the formation of midline commissures and the competency of tangential migration in ventral telencephalic neurons. J. Neuroscience 27(14):3884-93. *co-senior authors.

Akbar, H, Kim, J, Funk, K, Cancelas, JA, Shang, X, Chen, L, Johnson, JF, Williams, DA, Zheng Y. (2007) Genetic and pharmacological evidence that Rac1 GTPase is involved in regulation of platelet secretion and aggregation. J Thromb Haemost. 5(8):1747-1755.

Yang, L., and Zheng, Y. (2007) Cdc42 – a signal coordinator in hematopoietic stem cell maintenance. Cell Cycle 6, 1445 - 1450.

Thomas, E. K., Cancelas, J. A., Chae, H.-D., Cox, A. D., Keller, P. J., Danilo Perrotti, Neviani, P., Druker, B. J., Setchell, K. D. R., Zheng, Y., Harris, C. E., and Williams, D. A. (2007) Rac guanosine triphosphatases represent integrating molecular therapeutic targets for BCR-ABL-induced myeloproliferative disease. Cancer Cell 12, 467-478.

Vanni C, Mancini P, Ottaviano C, Ognibene M, Parodi A, Merello E, Russo C, Varesio L, Zheng Y, Torrisi MR, Eva A (2007) Ga13 regulation of proto-Dbl signaling. Cell Cycle 6(16):2058-70.

Liu, N., Zhang, G., Bi, F., Pan, Y., Xue, Y., Shi, Y., Zheng, Y., and Fan, D. (2007) RhoC is essential for gastric cancer metastasis. J. Mol. Medicine 85(10):1149-1156.

Yang, L, Wang, L, Kalfa, T, Cancelas, JA, Shang, X, Pushkaran, S, Mo, J, Williams, DA, Zheng, Y. (2007) Cdc42 critically regulates the balance between myelopoiesis and erythropoiesis. Blood 110: 3853 - 3861.

Chan, A, Akhtar, M, Brenner, M, Zheng, Y, Gulko, PS, and Symons, M. (2007) The small GTPase Rac1 regulates the proliferation and invasion of fibroblast-like synoviocytes from rheumatoid arthritic patients. Mol Med. 13(5-6):297-304.

Yang, L., Wang, L., Cancelas, J., Geiger, H., Mo, J., and Zheng, Y. (2007) The Rho GTPase Cdc42 coordinates hematopoietic stem cell quiescence and niche interaction in the bone marrow. Proc. Natl. Acad. Sci. U.S.A. 104:5091-5096.

Castilho R. M., Squarize C. H., Patel V., Millar S. E., Zheng Y., Molinolo A., Gutkind, J. S. (2007) Requirement of Rac1 distinguishes follicular from interfollicular epithelial stem cells. Oncogene 26,5078-5085.

Shang, X., Moon, S. Y., and Zheng, Y. (2007) p200 RhoGAP promotes cell proliferation by mediating cross-talk between Ras and Rho signaling pathways. J. Biol. Chem. 282:8801-8811.

Guo, D., Tan, Y., Wang, D., Madhusoodanan, K. S., Zheng, Y., Maack, T., Zhang, J. J., and Huang, X.-Y. (2007) A Rac-cGMP signaling pathway. Cell 128, 341-356.

Wang, L., Yang, L., Debidda, M., Witte, D., and Zheng, Y. (2007) Cdc42 GTPase-activating protein deficiency promotes genomic instability and premature aging-like phenotypes. Proc. Natl. Acad. Sci. U.S.A. 104: 1248-1253.

Chaturvedi, L. S., Marsh, H. M., Shang, X., Zheng, Y., and Basson, M. D. (2007) Repetitive deformation activates FAK and ERK mitogenic signals in human Caco-2 intestinal epithelial cells via Src and Rac1. J. Biol. Chem. 282(1):14-28.

Yang, C. H., Wei, L., Pfeffer, S., Du, Z., Murti, A., Valentine, W. J., Ransohoff, R. M., Zheng, Y., and Pfeffer, L. M. (2007) Identification of CXCL11 as a STAT3-dependent gene induced by interferon. J. Immunology 178(2):986-92.

Wang, L., and Zheng, Y. (2007) Cell type specific function of Rho GTPases revealed by gene targeting in mice. Trends Cell Biol. 17, 58-64.

Debidda, M., Williams, D. A., and Zheng, Y. (2006) Rac1 GTPase regulates cell genomic stability and senescence. J. Biol. Chem. 281: 38519 - 38528.

Wang, D., Tan, Y.-C., Kreitzer, G. E., Nakai, Y., Shan, D., Zheng, Y., and Huang, X.-Y. (2006) G protein G12 and G13 control the dynamic turnover of dorsal ruffles. J. Biol. Chem. 281, 32660-32667.

Xing, Z., Ryan, M.A., Daria, D., Nattamai, K. J., Van Zant, G., Wang, L., Zheng, Y., and Geiger, H. (2006) Increased hematopoietic stem cell mobilization in aged mice. Blood 108(7):2190-7.

Szczur, K., Xu, H., Atkinson, S., Zheng, Y., and Filippi, M.-D. (2006) Rho GTPase Cdc42 separately regulates directed migration versus random movement in neutrophils. Blood 108(13):4205-13.

Chen, L., Liao, G., Yang, L., Campbell, K., Nakafuku, M., Kuan, C., and Zheng, Y. (2006) Cdc42 deficiency causes sonic hedgehog-independent holoprosencephaly. Proc. Natl. Acad. Sci. U.S.A. 103, 16520-16525.

Kalfa, T. A., Pushkaran, S., Mohandas, N., Hartwig, J. H., Johnson, J. F., Joiner, C. H., Williams, D. A., and Zheng, Y. (2006) Rac GTPases regulate the morphology and deformability of the erythrocyte cytoskeleton. Blood 108(12), 3637-3645.

Yang, L., Wang, L., and Zheng, Y. (2006) Gene targeting of Cdc42 and Cdc42GAP affirms the critical involvement of Cdc42 in filopodia formation, directed migration, and proliferation in primary mouse embryonic fibroblasts. Mol. Biol. Cell 17: 4675-4685.

Ghiaur, G., Lee, A., Bailey, J., Cancelas, J. A., Zheng, Y., and Williams, D. A. (2006) Inhibition of RhoA GTPase activity enhances hematopoietic stem and progenitor cell proliferation and engraftment in vivo. Blood 108(6):2087-94.

Guo, F., Debidda, M., Yang, L., Williams, D. A., and Zheng, Y. (2006) Genetic deletion of Rac1 reveals its critical role in actin stress fiber formation and focal adhesion complex assembly. J. Biol. Chem. 281, 18652-9.

Gu, Y., Siefring, J. E., Wang, L., Chae, H. D., Bailey, J. R., and Zheng, Y. (2006) Oncogenic Vav1 induces Rac-dependent apoptosis via inhibition of Bcl-2 family proteins and collaborates with p53 deficiency to promote hematopoetic progenitor cell proliferation. Oncogene 25, 3963-72.

Nakai, Y., Zheng, Y., MacCollin, M., and Ratner, N. (2006) Temporal control of Rac in Schwann cell - axon interaction is disrupted in NF2-mutant schwannoma cells. J. Neuroscience 26(13):3390-5.

Nassar, N., Cancelas, J., Zheng, J., Williams, D. A., and Zheng, Y. (2006) Structure-function based design of small molecule inhibitors targeting Rho family GTPases. Curr Top Med Chem. 6(11):1109-16.

Wang, L., Yang, L., Fillipi, M., Williams, D.A. and Zheng, Y. (2006) Deletion of Cdc42GAP reveals a role of Cdc42 in erythropoiesis and hematopoietic stem/progenitor cell survival, migration and engraftment. Blood 107, 98-105.

Xue, Y., Bi, F., Zhang, X., Zhang, S., Pan, Y., Liu, N., Shi, Y., Yao , X., Zheng , Y., and Fan, D. (2006) Role of Rac1 and Cdc42 in hypoxia induced p53 and von Hippel-Lindau suppression and HIF1a activation. Int. J. Cancer 118, 2965-2972.

Nusser, N., Gosmanova, E., Makarova, N., Fujiwara, Y., Yang, L., Guo, F., Luo, Y., Zheng, Y., and Tigyi, G. (2006) Serine phosphorylation differentially affects RhoA binding to effectors: Implications to NGF-induced neurite outgrowth. Cell Signal. 18, 704-714.

Akbar, H., Cancelas, J., Williams, D. A., Zheng, J., and Zheng, Y. (2006) Rational design and applications of a Rac GTPase-specific small molecule inhibitor. Methods Enzymol. 406, 554-565.

Professional Organization Memberships

  • American Society for Biochemistry and Molecular Biology
  • American Society for Microbiology
  • American Association for the Advancement of Science
  • American Society of Hematology

Special Interests

Cell signaling through Rho family GTPases