Cell-cell communication (or induction) is a fundamental and prevalent mechanism that controls cell growth, cell fate determination and pattern formation of multicellular organisms. We are studying the nature of inductive signals, how inductive signals are generated and interpreted by cells, and how misregulation of cell signaling may cause diseases such as cancers. Induction 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 controls the proteolytic processing and activity of Cubitus interruptus (Ci), a zinc-finger transcription factor that transduces Hh signal into the nuclei. We have identified another Hh signaling component called Slimb, which belongs to the F-box protein family and is involved in the ubiquitin/proteasome pathway. Currently, we are testing the model in which Slimb acts in conjunction with PKA to regulate the proteolysis of Ci. 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 recruiting Cos2/Fu/Ci complexes through its carboxy-terminal tail. We are investigating how Smo/Cos2 complex activates Ci. In addition, we are exploring the mechanism by which Smo is activated by Hh. We have applied similar genetic, molecular and biochemical approaches to tackle other new components in the Hh and related pathways. For example, we identified a novel component in the Hh pathway named cmn (central missing), which encodes a member of membrane-bound acyltransferase that regulates Hh signaling activity by lipid modification of the Hh protein. Finally, we are 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 number of genes whose loss-of-function results in larger organ size or tumor like growth. We have recently discovered that the Drosophila homolog of MST Ser/Thr kinases functions as a tumor suppressor. We demonstrated that dMST/Hippo forms a complex with two other tumor suppressors, Sav and Wts, to control organ size by restricting cell proliferation and promoting apoptosis. We are exploring the upstream regulators and downstream effectors of this tumor suppressor complex.
RESEARCH INTERESTS
Cell signaling pathways important for animal development and human diseases.
Hedgehog and Wnt signal transduction pathways.
Genes and pathways involved in cell growth, differentiation, and pattern
Tumor suppressor genes and mechanism of oncogenesis.
RECENT PUBLICATIONS
Lei Zhang, Fangfang Ren, Qing Zhang, Yongbin Chen, Bing Wang, and Jin Jiang, "The TEAD/TEF family of transcription factor Scalloped mediates Hippo signaling in organ size control" Developmental Cell, 14:377-387, March 2008
Yun Zhao, Chao Tong, and Jin Jiang, "Hedgehog regulates Smoothened activity by inducing a conformational switch" Nature (article), 450,:252-258, November 2007
Qing Zhang, Lei Zhang, Bing Wang, Chan-Yen Ou, Cheng-Ting Chien, and Jin Jiang., "A Hedgehog-induced BTB protein modulates Hedgehog signaling responses by degrading Ci/Gli transcription factor" Developmental Cell, 10:719-729, June 2006
Jia, J., Ho, F., Tong, C., Zhang, Q., Wang, G., Wang, B., Amanai, K., and Jiang, J, "Phosphorylation of Cubitus interruptus by Double-time/CKIbeta and CKIalpha targets it for Slimb/beta-TRCP mediated proteolytic processing" Dev. Cell, 9:819-830, 2005
Jianhang Jia, Chao Tong, Bing Wang, Liping Luo and Jin Jiang, "Hedgehog Signalling Activity of Smoothened Requires Phosphorylation by Protein Kinase A and Casein Kinase I" Nature, 432:1045-1050, 2004
SIGNIFICANT PUBLICATIONS
Yun Zhao, Chao Tong, and Jin Jiang, "Hedgehog regulates Smoothened activity by inducing a conformational switch" Nature (article), 450:252-258, 2007
Jianhang Jia, Kazuhito Amanai, Gelin Wang, Bing Wang, Jiong Tan, and Jin Jiang, "Sgg/GSK-3 inhibits Hedgehog signaling by regulating Cubitus interruptus" Nature, 416:548-552, 2002
Jin Jiang and Gary Struhl., "Regulation of the Hedgehog and Wingless signaling pathways by the F-box/WD40 protein Slimb." Nature, 391:493-496, 1998
Jin Jiang and Gary Struhl, "Complementary and mutually exclusive activities of Decapentaplegic and Wingless organize axial patterning during Drosophila leg development." Cell, 86:401-409, 1996
Jin Jiang and Gary Struhl., "Protein Kinase A and Hedgehog Signaling in Drosophila Limb Development." Cell, 80:563-572, 1995
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