PDZ-dependent jagged 1 signaling in tumorigenesis

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DESCRIPTION (provided by applicant): A developing paradigm in signal transduction is that of the importance of cell-to-cell mediated signaling. How cells communicate between each other to develop and maintain specific cellular environments remains a poorly understood problem. Moreover, it is becoming increasingly clear that cellular microenvironments are critical to the initiation and maintenance of tumorigenesis. The Notch/DSL (Delta/Serrate/Lag-2) system is an excellent prototype for this type of signaling because it primarily mediates communication between adjacent non-equivalent cells. Jagged1 (Jag1), a member of the DSL family, is an evolutionarily conserved transmembrane protein that regulates cell fate decisions in numerous tissues. Additionally, aberrant misexpression of Jagged1 has been documented in several human tumors such as colon and cervical carcinomas; however, a causal role in oncogenesis has not been demonstrated. The current Notch/DSL signaling model proposes that a DSL protein on one cell is presented to a Notch protein on an adjacent cell thereby initiating signaling in the Notch-expressing cell. However, data from our laboratory indicates an alternative model whereby signaling is actually bi-directional. That is, we have demonstrated that expression of Jagged1 in RKE cells results in alterations in gene expression and cellular transformation. These activities are dependent on the presence of a PDZ-ligand domain at the C-terminus of Jagged1. Therefore, our underlying hypothesis is that Jagged1 induces intrinsic PDZ-dependent signaling events that can lead to oncogenic transformation of cells. The outlined experimental strategy will employ the use of cell-based and animal model systems to help elucidate the mechanism(s) through which Jagged1 induces transformation. The aims of this study are: (1) Determine the role of Jagged1-mediated signaling in cellular transformation and in tumor formation and maintenance, including defining the significance of the PDZ-ligand and other functional domains of Jagged1, (2) Elucidate the mechanism of Jagged1 downstream signaling events. Jagged1 interacting proteins (JIPs) and the importance of cell-to-cell signaling will be investigated, (3) Determine Jagged1-mediated changes in gene expression and investigate subsequent effects on cellular processes. These studies will establish a novel signaling paradigm in the Notch/DSL signaling mechanism and provide insights into complex cell-to-cell signaling in tumor microenvironments, which may provide novel therapeutic targets. PUBLIC HEALTH RELEVANCE: Notch is a gene that has been determined to contribute to the formation of leukemia and much work has been done to define the cellular events mediated by Notch that lead to changes in the cell that make them cancerous. We have shown that Notch's ligand, Jagged1, may also contribute to cellular transformation. It is essential to determine how this novel signaling mechanism in the Notch/DSL pathway may contribute to tumorigenesis.