PLENARY LECTURES

Fgf Signaling Pathways in Mouse Development

Professor Philippe Soriano

Professor Philippe Soriano
Department of Developmental and Regenerative Biology
Icahn School of Medicine at Mount Sinai
New York

Professor Philippe Soriano is an accomplished mouse geneticist whose research has focused on cell signaling pathways in development. He received his graduate training in France, did postdoctoral work in Germany and at the Whitehead Institute with Rudolf Jaenisch, and has assumed faculty positions at Baylor College of Medicine, the Fred Hutchinson Cancer Research Center and Mt. Sinai. He was a pioneer in using targeted gene knock-outs to study the gene function. His more recent research focuses on the study of signaling specificity downstream of PDGFs and FGFs in the embryo, particularly as it relates to craniofacial development.

Abstract
FGF signaling governs multiple processes important in development and disease. Many lines of evidence have implicated Erk1/2 as the predominant effector pathway downstream of Fgfrs, but these receptors can also signal through other mechanisms. To better understand the function of Erk1/2-independent signaling downstream of Fgfrs in the mouse, we have engineered allelic series of knock-in point mutations designed to disrupt Fgfr1 and Fgfr2 signaling functions individually and in combination. Multiple developmental contexts were affected including preimplantation, posterior outgrowth, limb patterning, skeletal development and craniofacial morphogenesis. Analysis of signaling mutants indicates that Frs2 binding to Fgfr1 and subsequent Erk1/2 engagement has the most pleiotropic functions in development, but that Crk proteins and Plcγ also contribute to Erk1/2 activation, providing a biochemical mechanism for additive signaling requirements. Frs2 engagement is surprisingly dispensable for Fgfr2 signaling. Genetic and biochemical evidence indicates that both receptors utilizes multiple pathways additively in vivo, and that the kinetics of signaling differ according to the cell type.

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Regulation of Host Innate Immunity by Mycobacterium Tuberculosis Secreted Effector Proteins

Professor Cuihua Liu

Professor Cuihua Liu
CAS Key Laboratory of Pathogenic Microbiology and Immunology
Institute of Microbiology
Chinese Academy of Sciences

Professor Cuihua Liu is a professor at the Institute of Microbiology, Chinese Academy of Sciences. Her laboratory is mainly interested in studying the molecular mechanisms of pathogenic bacteria-host interactions, focusing on elucidating the regulatory roles of protein modifications during those processes. Bacterial pathogens secrete effector proteins into host cells, which usually modulate the function of key signaling molecules in host cells in order to promote the bacterial survival and latent infections. In addition, many kinds of protein modifications such as ubiquitylation and phosphorylation can regulate key cellular signaling pathways during bacterial infection. Using pathogens such as M. tuberculosis as the model, Professor Cuihua Liu's group have identified several bacterial secreted proteins and host molecules modulating bacterial intracellular survival as well as host innate immune signaling pathways. Results from those studies could provide novel knowledge and specific targets for the development of pathogen-host interfaces-targeted anti-tuberculosis therapeutics. Professor Cuihua Liu has published more than 30 papers in peer-reviewed journals including Cell, Nature Immunology, PNAS, etc.

Abstract
Many pathogenic bacteria have evolved sophisticated strategies, including the secretion of effector proteins into mammalian cells, to subvert host innate immunity, thereby allowing those bacteria to avoid elimination and to survive within the hostile environment of macrophages for long periods of time. In addition, many kinds of protein modifications regulate key cellular signaling pathways during bacterial infection. Suppression of NF-κB and MAPK may be critical for successful intracellular survival of Mycobacterium tuberculosis, but the mechanisms by which specific mycobacterial effectors exploit signaling pathways of the host innate immune system remain largely unclear. We thus are most interested in identifying pathogen virulence factors, focusing on elucidating the regulatory roles of host protein modification systems such as ubiquitination and phosphorylation during pathogen-host interactions. Using M. tuberculosis as the model, we have identified several secreted bacterial effectors which can modulate signaling pathways of the host innate immune system. We recently revealed that M. tuberculosis PtpA, a secreted tyrosine phosphatase essential for tuberculosis pathogenicity, suppresses innate immunity dependent on JNK/p38 MAPK and NF-κB pathways by exploiting host ubiquitin system. Binding of PtpA to ubiquitin via a region with no homology to human proteins activated it to dephosphorylate phosphorylated JNK and p38, leading to suppression of innate immunity. Furthermore, the host adaptor TAB3 mediated NF-κB signaling by sensing ubiquitin chains, and PtpA blocked this process by competitively binding the ubiquitin-interacting domain of TAB3 (Wang J et al., Nature Immunology, 2015). In another study, we discovered a novel mechanism by which M. tuberculosis Mce3E suppresses host innate immune responses through inhibiting the ERK1/2 signaling pathway. Specifically, we demonstrated that Mce3E inhibits the activation of the ERK1/2 signaling pathway, leading to the suppression of Tnf and Il6 expression, and the promotion of mycobacterial survival within macrophages. Mce3E interacts and colocalizes with ERK1/2 at the endoplasmic reticulum in a DEF motif (an ERK-docking motif)–dependent manner, relocates ERK1/2 from cytoplasm to the endoplasmic reticulum, and finally reduces the association of ERK1/2 with MEK1 and blocks the nuclear translocation of phospho-ERK1/2 (Li J et al., The Journal of Immunology, 2015). Collectively, M. tuberculosis secretes a variety of effector proteins which can interact with multiple host proteins to regulate host innate immunity, thus promoting intracellular survival of pathogens.

Key words
Mycobacterium tuberculosis; effector proteins; ubiquitination; phosphorylation; innate immunity

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Wnt Signaling in Regulating Mammary Stem Cell and Breast Cancer

Dr Yi Zeng
Professor Yi Zeng
Institute of Biochemistry and Cell Biology,
Shanghai Institute of Biological Science,
Chinese Academy of Sciences

Yi Arial Zeng did her PhD at Simon Fraser University in Canada with Dr. Esther Verheyen and postdoctoral work at Stanford University in the laboratory of Dr. Roel Nusse. She has been a principal investigator at Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences since 2010.

Her research interest is to reveal the identity of adult stem cells, understand their regulatory mechanisms, determine how these mechanisms have been hijacked in diseases, and learn how to manipulate the key players for the purposes of regenerative and cancer medicine. She currently focuses her research efforts on mammary stem cells and breast cancers.

Abstract
The mammary gland is composed of multiple types of epithelial cells that are generated by mammary stem cells (MaSCs) residing at the top of the hierarchy. The identity of MaSCs is unknown. Our study demonstrates that Procr (Protein C receptor), a novel Wnt-target in the mammary gland, marks a population of multipotent MaSC. Procr-expressing cells display high regenerative capacity in transplantation assays and differentiate into all lineages of the mammary epithelium by lineage tracing. These results define a novel multipotent mammary stem cell population that could be important in the initiation of breast cancer. Triple-negative breast cancer (TNBC) is a highly aggressive malignancy with no targeted treatment option. We found that PROCR is highly expressed in TNBC patient samples, and associated with poor prognosis. Remarkably, targeting PROCR by a neutralizing antibody inhibits TNBC tumor growth. PROCR represents a surface therapeutic target for human TNBC.

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