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 Nrdp1 that mediates the ubiquitination of ErbB receptors, thereby promoting their trafficking to degradative cellular compartments. The hypothesis guiding these studies is that the Nrdp1 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 Nrdp1 activity is regulated, and to understand the contribution of the Nrdp1 pathway to ErbB receptor-induced mammary tumor growth and progression. These goals will be addressed with three specific aims. 1) The regulation of Nrdp1 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 Nrdp1 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 Nrdp1 on the growth of ErbB-induced mammary tumors in transgenic mouse models will be determined. These studies will assess whether overexpression of wild-type Nrdp1 in the mouse mammary gland can suppress the latency, growth and metastasis of ErbB-induced mammary tumors, and whether overexpression of dominant-negative Nrdp1 can induce mammary tumor formation or potentiate the latency or growth of ErbB-induced tumors. The results of these studies could implicate the Nrdp1 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. ? ? ?

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Tumor Cell Biology Study Section (TCB)
Program Officer
Sussman, Daniel J
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University of California Davis
Internal Medicine/Medicine
Schools of Medicine
United States
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Printsev, Ignat; Curiel, Daniel; Carraway 3rd, Kermit L (2016) Membrane Protein Quantity Control at the Endoplasmic Reticulum. J Membr Biol :
Savoy, Rosalinda M; Chen, Liqun; Siddiqui, Salma et al. (2015) Transcription of Nrdp1 by the androgen receptor is regulated by nuclear filamin A in prostate cancer. Endocr Relat Cancer 22:369-86
Hatakeyama, Jason; Wald, Jessica H; Printsev, Ignat et al. (2014) Vangl1 and Vangl2: planar cell polarity components with a developing role in cancer. Endocr Relat Cancer 21:R345-56
Printsev, Ignat; Yen, Lily; Sweeney, Colleen et al. (2014) Oligomerization of the Nrdp1 E3 ubiquitin ligase is necessary for efficient autoubiquitination but not ErbB3 ubiquitination. J Biol Chem 289:8570-8
Rafidi, Hanine; Mercado 3rd, Francisco; Astudillo, Michael et al. (2013) Leucine-rich repeat and immunoglobulin domain-containing protein-1 (Lrig1) negative regulatory action toward ErbB receptor tyrosine kinases is opposed by leucine-rich repeat and immunoglobulin domain-containing protein 3 (Lrig3). J Biol Chem 288:21593-605
Hong, Shiao-Ya; Shih, Yi-Ping; Li, Tianhong et al. (2013) CTEN prolongs signaling by EGFR through reducing its ligand-induced degradation. Cancer Res 73:5266-76
Liu, Wei; Hsu, Daniel K; Chen, Huan-Yuan et al. (2012) Galectin-3 regulates intracellular trafficking of EGFR through Alix and promotes keratinocyte migration. J Invest Dermatol 132:2828-37
Tili, Esmerina; Michaille, Jean-Jacques; Wernicke, Dorothee et al. (2011) Mutator activity induced by microRNA-155 (miR-155) links inflammation and cancer. Proc Natl Acad Sci U S A 108:4908-13
Fry, William H D; Simion, Catalina; Sweeney, Colleen et al. (2011) Quantity control of the ErbB3 receptor tyrosine kinase at the endoplasmic reticulum. Mol Cell Biol 31:3009-18
Albrecht, Huguette; Carraway 3rd, Kermit L (2011) MUC1 and MUC4: switching the emphasis from large to small. Cancer Biother Radiopharm 26:261-71

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