The aberrant overexpression and concomitant activation of members of the ErbB family of growth factor receptor tyrosine kinases plays key roles in promoting the growth and progression of a variety of solid tumor types. The long-term objective of the proposed studies is to understand the role of a novel protein degradation pathway in regulating ErbB-induced tumor progression. A central component of the pathway is a RING finger E3 ubiquitin ligase called Nrdpl that mediates the ubiquitination of ErbB receptors, thereby promoting their trafficking to degradative cellular compartments. The hypothesis guiding these studies is that the Nrdpl protein degradation pathway regulates ErbB-mediated cellular growth signaling by governing receptor levels through degradation. The two overarching goals for the current funding period are to understand the molecular mechanisms by which Nrdpl activity is regulated, and to understand the contribution of the Nrdpl pathway to ErbB receptor-induced mammary tumor growth and progression. These goals will be addressed with three specific aims. 1) The regulation of Nrdpl stability and activity by growth factors, signaling kinases and deubiquitinating enzymes will be examined using biochemical and molecular biological methods. The interactions among proteins involved in the pathway will also be examined. 2) The impact of the overexpression or loss of Nrdpl pathway components on the growth properties of cultured mouse and human mammary tumor cell lines will be examined using assays that measure proliferation, survival, motility and invasion. 3) The impact of Nrdpl on the growth of ErbB-induced mammary tumors in transgenic mouse models will be determined. These studies will assess whether overexpression of wild-type Nrdpl in the mouse mammary gland can suppress the latency, growth and metastasis of ErbB-induced mammary tumors, and whether overexpression of dominant-negative Nrdpl can induce mammary tumor formation or potentiate the latency or growth of ErbB-induced tumors. The results of these studies could implicate the Nrdpl pathway as a suppressor of tumor cell growth and progression, in turn suggesting that restoration or augmentation of pathway function in tumors could offer therapeutic benefit.
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