Key words: signal transduction, pattern formation and growth control, tumor suppressor gene, control of adult stem cell proliferation, tissue regeneration
Cell-cell communication (cell signaling) is a fundamental and prevalent mechanism that controls cell growth, cell fate determination and pattern formation of multicellular organisms. We are interesting in studying how inductive signals are generated and interpreted by cells, and how misregulation of cell signaling may cause diseases such as cancer.
Cell-cell communication is often mediated by conserved signaling pathways, such as Hedgehog (Hh) and Wingless (Wg)/Wnt pathways. Mutations in genes of Hh and Wg/Wnt pathways have been linked to several types of cancers including basal cell carcinomas, the most common cancer afflicting some 750,000 people every year in the United States alone. The Hh and Wg/Wnt pathways are operating in a similar way among organisms as different as Drosophila and human, which means that we can use animal models to study these important pathways.
We have been carrying out systematic genetic screens to identify genes controlling pattern formation and growth of Drosophila adult organs. Toward this end, we have identified many novel components in the Hh, Wg and other signaling pathways. For example, our genetic screen has led to an unexpected and important discovery that the cAMP dependent protein kinase, PKA, plays a pivotal role in regulating Hh signal transduction. We found that PKA acts in concert with GSK3, CK1 and an E3 ubiquitin ligase SCFSlimb to control the proteolytic processing and activity of Cubitus interruptus (Ci), a member of Gli family of zinc-finger transcription factor that transduces Hh signal into the nuclei. Ci forms protein complexes with the kinesin-like protein Costal2 (Cos2), the Ser/Thr kinase Fused (Fu), and the tumor suppressor protein Su(fu). We found that this complex regulates subcellular localization and proteolytic processing of Ci. We are investigating the biochemical mechanisms by which complex formation regulates different aspects of Ci.
Hh transduces signal by binding to the multi-span transmembrane protein Patched (Ptc), leading to the activation of the seven-transmembrane protein Smoothened (Smo). We discovered that Smo transduces Hh signal by physically interacting Cos2/Fu/Ci complexes. In response to Hh, Smo is phosphorylation by PKA and CK1, leading to its cell surface accumulation and active conformation. We are investigating how Smo phosphorylation and trafficking are regulated and how different levels of Hh signal are transduced by Smo to activate Ci. In addition, we apply similar genetic, molecular and biochemical approaches to tackle other new components in the Hh and related pathways.
We are also interested in understanding how cell growth and organ size are regulated and how growth and patterning are coordinated. Toward this end, we have identified a new tumor suppressor pathway, called Hippo (Hpo) signaling pathway, which controls organ size by restricting cell proliferation and promoting apoptosis in both Drosophila and mammals. We found that KO of mammalian homologues of Hpo (MST1/2) leads to liver cancer. We are exploring the upstream regulators and downstream effectors of Hpo tumor suppressor pathway.
Finally, we are interested in the mechanisms that control adult stem cell proliferation, tissue homeostasis and regeneration. We found that Drosophila adult intestine stem cells undergo excessive proliferation and differentiation to replenish lost cells in response to tissue damage. We are studying how tissue injury leads to changes in stem cell behaviors.
Awards & Honors
- CPRIT Individual investigator award
- Eugene Mc Dermott Scholar in Biomedical Research, UT Southwestern
- Leukemia & Lymphoma Society Scholar Award
- Searle Scholars, The Chicago Community Trust
Jiang, J. and Struhl, G. 1995. Protein Kinase A and Hedgehog Signaling in Drosophila Limb Development. Cell 80: 563-572.
Jiang, J. and Struhl, G. 1996. Complementary and mutually exclusive activities of ecapentaplegic and Wingless organize axial patterning during Drosophila leg development. Cell 86: 401-409.
Jiang, J. and Struhl, G. 1998. Regulation of the Hedgehog and Wingless signaling pathways by the F-box/WD40 protein Slimb. Nature 391: 493-496.
Spencer, E., Jiang, J., and Chen, Z.J. 1999. Signal-induced ubiquitination of IkBa by the F-box protein, Slimb/b-TrCP. Genes & Development. 13:284-294.
Wang, G., Wang, B., and Jiang, J. 1999. Protein kinase A antagonizes Hedgehog signaling by regulating both the activator and repressor forms of Cubitus interruptus. Genes & Development. 13:2828-2837.
2000 - 2010
Wang, G., Amanai, K., Wang, B., and Jiang, J. 2000. Interactions with Costal2 and Suppressor of fused regulates nuclear translocation and activity of Cubitus interruptus. Genes & Development 14: 2893-2905.
Amanai, K. and Jiang, J. (2001). Distinct roles of Central missing and Dispatched in sending the Hedgehog signal. Development 128, 5119-27.
Jia, J., Amanai, K., Wang, W., Tang, J., Wang, B., and Jiang, J. 2002. Shaggy/GSK3 antagonizes Hedgehog signaling by regulating Cubitus interruptus. Nature 416, 548-52
Hyuk Wan Ko, Jin Jiang, and Isaac Edery. 2002. A role for Slimb in the degradation of Drosophila PERIOD protein phosphorylated by DOUBLETIME. Nature 420, 673-678.
Jin Jiang. 2002. Degrading Ci: Who is Cul-pable? 16, 2315-2321.
Jianhang Jia, Chao Tong, and Jin Jiang . 2003. Smoothened transduces Hedgehog signal by physically interacting with Costal2/Fused complex through its carboxyl-terminal tail. Genes & Development 17, 2709-2720.
Jianhang Jia, Wensheng Zhang, Bing Wang, Richard Trinko, and Jin Jiang. 2003. The Drosophila Ste20 family kinase dMST functions as a tumor suppressor by restricting cell proliferation and promoting apoptosis. Genes & Development 17, 2514-2519.
Jianhang Jia, Chao Tong, Bing Wang, Liping Luo and Jin Jiang. 2004. Hedgehog Signalling Activity of Smoothened Requires Phosphorylation by Protein Kinase A and Casein Kinase I. Nature 432, 1045-1050.
Wensheng Zhang, Yun Zhao, Chao Tong, Geling Wang, Bing Wang, Jianhang Jia, and Jin Jiang. 2005. Hedgehog-regulated Costal2/kinase complexes control phosphorylation and proteolytic processing of Cubitus interruptus. Developmental Cell, 8, 267-278.
Atish Ganuly, Jin Jiang, and Y. Tony IP. 2005. Wnt8 is a target and an inhibitor of the Dorsal Twist Snail network in the gastrulating Drosophila embryo. Development, 132, 3419-3429
Jia, J., Ho, F., Tong, C., Zhang, Q., Wang, G., Wang, B., Amanai, K., and Jiang, J. (2005). Phosphorylation of Cubitus interruptus by Double-time/CKIe and CKIa targets it for Slimb/b-TRCP mediated proteolytic processing. Developmental Cell 9, 819-830.
Qing Zhang, Lei Zhang, Bing Wang, Chan-Yen Ou, Cheng-Ting Chien, and Jin Jiang. 2006. A Hedgehog-induced BTB protein modulates Hedgehog signaling responses by degrading Ci/Gli transcription factor. Developmental Cell 10, 719-729.
Lei Zhang, Jianhang Jia, Bing Wang, Kazuhito Amanai, Keith A. Wharton, Jr.1, and Jin Jiang. 2006. Regulation of Wingless signaling by the CKI family in Drosophila limb development. Developmental Biology 299 (1): 221-237.
Yajuan Liu, Xuesong Cao, Jin Jiang, and Jianhang Jia. 2007. Fused-Costal2 protein complex regulates Hedgehog-induced Smo phosphorylation and cell-surface accumulation. Genes & Development 21(15):1949-63.
Yun Zhao, Chao Tong, and Jin Jiang. 2007. Hedgehog regulates Smoothened activity by inducing a conformational switch. Nature (article) 450, 252-258.
Lei Zhang, Fangfang Ren, Qing Zhang, Yongbin Chen, Bing Wang, and Jin Jiang. 2008. The TEAD/TEF family of transcription factor Scalloped mediates Hippo signaling in organ size control. Developmental Cell 14, 377-387.
Jin Jiang and C-C Hui. 2008. Hedgehog Signaling in Development and Cancer. Developmental Cell 15 801-812
Alla Amcheslavsky, Jin Jiang, Y. Tony Ip. 2009. Tissue damage-induced intestinal stem cell division in Drosophila. Cell Stem Cell 4, 49-61.
Qing Zhang, Qing Shi, Yongbin Chen, Tao Yue, Shuang Li, Bing Wang, and Jin Jiang. 2009. Multiple Ser/Thr rich degrons mediate the degradation of Ci/Gli by the Cul3-HIB/SPOP E3 ubiquitin ligase. PNAS 106, 21191-21196.
Fangfang Ren, Lei Zhang, and Jin Jiang. 2010. Hippo signaling regulates Yorkie nuclear localization and activity through 14-3-3 dependent and independent mechanisms. Dev Biology 337, 303-312.
Hai Song, Kingston Mak, Lilia Topol, Kangsun Yun, Jianxin Hu, Lisa Garrett, Yongbin
Chen, Ogyi Park, Jia Chang, R. Mark Simpson, Cun-Yu Wang, Bin Gao, Jin Jiang and
Yingzi Yang. 2010. Mammalian Mst1 and Mst2 kinases play essential roles in organ size control and tumor suppression. PNAS 107(4):1431-6.
Yongbin Chen, Shuang Li, Chao Tong, Bing Wang, Yajuan Liu, Jianhang Jia and Jin
Jiang. 2010. G protein coupled receptor kinase 2 regulates high-level Hedgehog signaling by promoting the active state of Smo through both kinase dependent and independent mechanisms. Genes & Development, 24, 2054-2067.
Fangfang Ren, Bing Wang, Tao Yue, Eun-Young Yun, Y.Tony Ip & Jin Jiang. 2010. Hippo signaling regulates Drosophila intestine stem cell proliferation through multiple pathways. PNAS 107(49):21064-9.
Hongge Jia, Yajuan Liu, Ruohan Xia, Chao Tong, Tao Yue, Jin Jiang, and Jianhang Jia. 2010. Casein Kinase 2 Promotes Hedgehog Signaling by Regulating both Smoothened and Cubitus Interruptus. Journal of Biological Chemistry 48, 37218-26.
Alla Amcheslavsky, Naoto Ito, Jin Jiang and Y. Tony Ip. 2011. Tuberous Sclerosis Complex restricts the growth but promotes the division of intestinal stem cells in Drosophila. Journal of cell Biology 193, 695-710.
Yongbin Chen, Noriaki Sasai, Guoqiang Ma, Tao Yue, Jianhang Jia, James Briscoe and Jin Jiang. 2011. Sonic Hedgehog Dependent Phosphorylation by CK1a and GRK2 is Required for Ciliary Accumulation and Activation of Smoothened. PLoS Biol 9(6): e1001083. doi:10.1371/journal.pbio.1001083
Sheu-Fen Lee, Bhooma Srinivasan, Chantelle F. Sephton, Daniel R. Dries, Bing Wang, Colleen M. Dewey, Cong Yu, Pradip K. Majumder, Sanjiv Shah, Jin Jiang2, and Gang Yu. 2011. Gamma-secretase-regulated proteolysis of notch by mitochondrial intermediate peptidase. Journal of Biological Chemistry 286, 27447-53.
Qing Shi, Shuang Li, Jianhang Jia and Jin Jiang. 2011. Hedgehog-induced Smoothened conformational switch assembles a signaling complex that activates Fused by promoting its dimerization and phosphorylation. Development 138, 4219-4231.
Chi-chung Hui and Jin Jiang. 2011. Hedgehog signaling activation in human cancer and its clinical implications. Springer Book Chapter, 1-17.
Shuang Li, Yongbin Chen, Qing Shi, Tao Yue, Bing Wang, and Jin Jiang, 2012. Hedgehog-regulated Ubiquitination Controls Smoothened Trafficking and Cell Surface Expression in Drosophila. PLoS Biol 10(1): e1001239. doi:10.1371/journal.pbio.1001239.
Yunyun Jin, Liang Dong, Yi Lu, Wenqing Wu, Qian Hao, Zhaocai Zhou, Jin Jiang, Yun Zhao and Lei Zhang. 2012. Dimerization and cytoplasmic localization regulate Hippo kinase signaling activity in organ size control. Journal of Biological Chemistry 287, 5784-96.
Yuxiao Wang, Huawei He, Nishi Srivastava, Sheikh Vikarunnessa, Yongbin Chen, Jin Jiang, Christopher Cowan & Xuewu Zhang. 2012. Plexins are GTPase Activating Proteins for Rap and Activated by Induced Dimerization. Science Signaling 5(207):ra6.
Tao Yue, Aiguo Tian, and Jin Jiang. 2012. The cell adhesion molecule Echinoid functions as a tumor suppressor and upstream regulator of the Hippo signaling pathway. Developmental Cell 22, 255-267.
Cuiping Yang, Wenlin Chen, Yongbin Chen and Jin Jiang. 2012. Smoothened transduces Hedgehog Signal by forming a complex with Evc/Evc2. Cell Res 22:1593–1604.
Yongbin Chen and Jin Jiang. 2013. Decoding the phosphorylation code in Hedgehog signal transduction. Cell Res 2, 186-200.
Zhao Zhang, Xiangdong Lv, Jin Jiang, Lei Zhang, Yun Zhao. 2013. Dual role of Hh signaling in the regulation of somatic stem cell self-renewal and germline stem cell maintenance in Drosophila testis. Cell Res 4, 573-576.
Hongling Huang, Shimin Wang, Meng-Xin Yin, Liang Dong, Chao Wang, Wei Wu, Yi Lu, Miao Feng, Chuanyang Dai, Xiaocan Guo, Li Li, Bin Zhao, Zhaocai Zhou, Hongbin Ji, Jin Jiang, Yun Zhao, Xin-yuan Liu and Lei Zhang. 2013. Par-1 Regulates Tissue Growth by Phosphorylating Hippo and Influencing the Function of Hippo-Salvador Complex. PLoS Biol 11(8):e1001620. doi: 10.1371/journal.pbio.1001620.
Fangfang Ren, Qing Shi, Yongbin Chen, Alice Jiang, Y. Tony Ip, Huaqi Jiang, and Jin Jiang. 2013. Drosophila Myc integrates multiple signaling pathways to regulate intestine stem cell proliferation during midgut regeneration. Cell Res in press.
A full list of Dr. Jiang's publications is available via PubMed