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Zheng Lab

Yi Zheng, PhD

Title

Katherine Stewart Waters Endowed Chair

Appointment

Professor of Pediatrics

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 - 03/31/2009
"Studies of Dbl-like regulators of small GTP-binding proteins"
The goals of this grant 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 GM60523 (PI: Yi Zheng)
National Institute of General Medicine 01/01/2000 - 06/30/2008
"Interaction of Rho GTPases with regulators and effectors"
The goal is to dissect the unique as well as the commonly shared structure-function features of individual members of Rho family GTPases, Rac1 in particular.

NIH R01 CA105117 (PI: Yi Zheng)
National Cancer Institute 03/01/2004 – 02/28/2009
"Rho GTPase-activating proteins in cancer"
The goals are to understand the function and regulation of a number of RhoGAP molecules and to determine their contribution to cancer cell growth and migration.

NIH R01 HL085362 (PI: Yi Zheng)
National Institute of Heart, Lung and Blood 07/01/2006 – 05/31/2011
"Cell type and stimulus specific signaling role of Cdc42 in blood"
The goal is to determine hematopoietic stem cell- and mast cell-specific roles of Cdc42 signaling by using Cdc42 and Cdc42GAP gene targeted mouse models.

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.

NIH R03 CA125830 (PI: Yi Zheng)
National Cancer Institute 09/15/2006 – 08/31/2008
"Targeting RhoA in Lymphomagenesis"
The goals are to validate a RhoA-targeting strategy in a lymphomagenic mouse model and to implicate RhoA as a useful cancer prevention and/or therapeutic target.

Publications, Most Recent

Connect to Yi Zheng's publications on PubMed

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.

Vanni, C., Ottaviano, C., Guo, F., Puppo, M., Varesio, L., Zheng, Y., and Eva, A. (2005) Constitutively active Cdc42 mutant confers growth disadvantage in cell transformation. Cell Cycle 4, 1675-1682.

Cancelas, J. A., Lee, A. W., Prabhakar, R., Stringer, K., Zheng, Y., and Williams, D. A. (2005) Rac1 and Rac2 GTPases distinctly regulate hematopoietic stem cell localization and are novel targets for stem cell mobilization. Nature Medicine 11(8):886-91.

Wang, L., Yang, L., Burns, K., Kuan, C.-Y., and Zheng, Y. (2005) Cdc42GAP regulates JNK-mediated apoptosis and cell number during mammalian perinatal growth. Proc. Natl. Acad. Sci. U.S.A. 102: 13484-13489.

Zhang, B., Yang, L., and Zheng, Y. (2005) Novel intermediate of Rac GTPase guanine nucleotide exchange reaction. Biochem Biophys Res Commun. 331, 413-421.

Mizrahi , A., Molshanski-Mor, S., Weinbaum, C., Zheng, Y., Hirshberg, M., and Pick, E. (2005) Activation of the phagocyte NADPH oxidase by Rac guanine nucleotide exchange factors in conjunction with ATP and Nucleoside Diphosphate Kinase. J. Biol. Chem. 280, 3802-3811.

Carstanjen, D., Yamauchi, A., Koorneef , A., Zang, H., Filippi, M.-D., Atkinson, S., Zheng, Y., Dinauer, M. C., and Williams, D. A. (2005) Rac2 Regulates Neutrophil Chemotaxis, Superoxide Production and Myeloid Colony Formation through Multiple Distinct Effector Pathways. J. Immunology 174(8):4613-4620.

Barwe, S. P., Anilkumar, G., Moon, S. Y., Zheng, Y., Whitelegge, J., Rajasekaran, S. A., and Rajasekaran, A. K. (2005) Novel Role for Na,K-ATPase in Phosphatidylinositol 3-Kinase Signaling and Suppression of Cell Motility. Mol Biol Cell. 16(3):1082-94.

Zhang, B., Zhang, Y., Shacter, E., and Zheng, Y. (2005) Mechanism of the guanine nucleotide exchange reaction of Ras GTPase – Evidence for a GTP/GDP displacement model. Biochemistry 44, 2566-2576.

Gu, Y., Zheng, Y., and Williams, D. A. (2005) RhoH GTPase: a key regulator of hematopoietic cell proliferation and apoptosis. Cell Cycle 4 (2), 201-202.

Felekkis, K. N., Narsimhan, R. P., Near, R., Castro, A. F., Zheng, Y., Quilliam, L. A., and Lerner, A. (2005) AND-34 activates phosphatidylinositol 3-kinase and induces antiestrogen resistance in a SH2 and GEF-like domain-dependent manner. Mol. Cancer Research 3(1):32-41.

Debidda, M., Wang, L., Zang, H., Poli, V., and Zheng, Y. (2005) A role of STAT3 in Rho GTPase regulated cell migration and proliferation. J. Biol. Chem. 280: 17275-17285.

Zhang , J., Deng , M., Parthasarathy, R., Wang, L., Mongan, M., Molkentin, J. D., Zheng, Y., and Xia, Y. (2005) MEKK1 transduces activin signals in keratinocytes to induce actin stress fiber formation and migration. Mol. Cell Biol. 25, 60-65.

Lim, M. A., Yang, L., Zheng, Y., Wu, H., Dong, L. Q., and Liu, F. (2004) Roles of PDK-1 and PKN in regulating cell migration and cortical actin formation of PTEN-knockout cells. Oncogene 23(58):9348-58.

Wang, L., Zhu, K., and Zheng, Y. (2004) Oncogenic Dbl, Cdc42, and p21-activated kinase form a functional signaling complex through the minimum interactive domains. Biochemistry 43, 14584-93.

Xue, Y, Bi, F, Zhang, X, Pan, Y, Liu, N, Zheng, Y, Fan, D. (2004) Inhibition of endothelial cell proliferation by targeting Rac1 GTPase with small interference RNA in tumor cells. Biochem Biophys Res Commun. 320, 1309-1315

Filippi, M.-D., Harris, C. E., Meller, J., Gu, Y., Zheng, Y., and Williams, D. A. (2004) Localization of Rac2 specifies superoxide generation, actin polarity and chemotaxis in neutrophils. Nature Immunology 5, 744-751.

Liu, N., Bi, F., Pan, Y., Sun, L., Xue, Y., Shi, Y., Zheng, Y., Fan, D. (2004) Reversal of the malignant phenotype of gastric cancer cells by inhibition of RhoA expression and activity. Clin. Cancer Res. 10(18):6239-6247.

Guo, F., and Zheng, Y. (2004) Rho family GTPases cooperate with p53 deletion to promote primary mouse embryonic fibroblast cell invasion. Oncogene 23, 5577-5585.

Skowronek, K. R., Guo, F., Zheng, Y., and Nassar, N. (2004) The C-terminal basic tail of RhoG assists the guanine nucleotide exchange factor Trio in binding to phospholipids. J. Biol. Chem. 279: 37895-37907.

Gao, Y., Dickerson, J. B., Guo, F., Zheng, J., and Zheng, Y. (2004) Rational design and characterization of a Rac GTPase-specific small molecule inhibitor. Proc. Natl. Acad. Sci. U. S. A. 101, 7618-7623.

Pan Y, Bi F, Liu N, Xue Y, Yao X, Zheng Y, Fan D. (2004) Expression of seven main Rho family members in gastric carcinoma. Biochem Biophys Res Commun. 315, 686-91.

Barac, A., Basile, J., Vázquez-Prado, J., Gao, Y., Zheng, Y., and Gutkind, J. S. (2004) Direct interaction of PAK4 with PDZ-RhoGEF, a G protein-linked Rho guanine exchange factor. J. Biol. Chem. 279, 6182-6189.

Cook-Mills JM, Johnson JD, Deem TL, Ochi A, Wang L, Zheng Y. (2004) Calcium mobilization and Rac1 activation are required for VCAM-1 (vascular cell adhesion molecule-1) stimulation of NADPH oxidase activity. Biochem. J. 378, 539-47.

Bebreceni, B., Gao, Y., Guo, F., Zhu, K., Jia, B., and Zheng, Y. (2004) Mechanism of guanine nucleotide exchange and Rac-mediated signaling revealed by a dominant negative Trio mutant. J. Biol. Chem. 279, 2777-2786.

Guo, F., and Zheng, Y. (2004) Involvement of Rho family GTPases in p19Arf or p53 mediated proliferation of primary mouse embryonic fibroblasts. Mol. Cell Biol. 24, 1426-1428.

Chikumi, H., Barac, A., Behbahani, B., Gao, Y., Teramoto, H., Zheng, Y., and Gutkind, J. S. (2004) Homo-and hetero-oligomerization of PDZ-RhoGEF,LARG and p115RhoGEF by their C-terminal region regulates their in vivo Rho GEF activity and transforming potential. Oncogene 23, 233-240.

Professional Organization Memberships

  • American Society for Biochemistry and Molecular Biology
  • American Society for Microbiology
  • American Association for the Advancement of Science
  • New York Academy of Sciences

Special Interests

Cell signaling through Rho family GTPases