Growth factor receptor tyrosine kinases (RTKs) play central roles in the development and maintenance of tissues, and their aberrant activation contributes to the growth and progression of a variety of tumor types. The long-term goal of the proposed project is to identify and characterize novel RTK negative regulatory pathways in an effort to better understand the mechanisms by which RTKs contribute to tumor progression. Efforts for the current funding period will focus on a novel human transmembrane leucine-rich repeat protein called LRIG1. LRIG1 physically interacts with each of the four members of the mammalian ErbB family of RTKs, enhances their ubiquitination and degradation, and suppresses ErbB-mediated proliferation and transformation of cultured cells. Our two overarching questions concern the biochemical mechanisms underlying ErbB negative regulation by LRIG1, and the participation of LRIG1 in ErbB signaling in vivo. These questions will be addressed with four specific aims. 1) The mechanisms underlying LRIG1-mediated receptor ubiquitination and degradation will be assessed by identifying the responsible E3 ubiquitin ligase(s). 2) Mutagenesis approaches will be employed to functionally dissect the LRIG1 molecule to identify regions responsible for interacting with ErbB receptors, and regions responsible for coupling receptors to the protein degradation machinery. Receptor structural elements responsible for LRIG1 interaction will also be identified. 3) The ability of LRIG1 to influence ErbB-mediated mammary tumor progression in a transgenic mouse model will be examined. These studies will involve crossing LRIG1-/- mice or mice inducibly overexpressing LRIG1 into an MMTV-ErbB2 line, and assessing tumor latency, growth rate and metastasis frequency. 4) The expression of LRIG1 in human breast tumors will be examined and correlated with ErbB receptor protein overexpression. The proposed project will lay the biochemical foundation for LRIG1 as a negative regulator of ErbB receptor function.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA118384-05
Application #
7848271
Study Section
Tumor Cell Biology Study Section (TCB)
Program Officer
Salnikow, Konstantin
Project Start
2006-07-01
Project End
2012-05-31
Budget Start
2010-06-01
Budget End
2012-05-31
Support Year
5
Fiscal Year
2010
Total Cost
$209,581
Indirect Cost
Name
University of California Davis
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
047120084
City
Davis
State
CA
Country
United States
Zip Code
95618
Wald, J H; Hatakeyama, J; Printsev, I et al. (2017) Suppression of planar cell polarity signaling and migration in glioblastoma by Nrdp1-mediated Dvl polyubiquitination. Oncogene 36:5158-5167
Hatakeyama, Jason; Wald, Jessica H; Rafidi, Hanine et al. (2016) The ER structural protein Rtn4A stabilizes and enhances signaling through the receptor tyrosine kinase ErbB3. Sci Signal 9:ra65
Yokdang, N; Hatakeyama, J; Wald, J H et al. (2016) LRIG1 opposes epithelial-to-mesenchymal transition and inhibits invasion of basal-like breast cancer cells. Oncogene 35:2932-47
Morrison, M M; Williams, M M; Vaught, D B et al. (2016) Decreased LRIG1 in fulvestrant-treated luminal breast cancer cells permits ErbB3 upregulation and increased growth. Oncogene 35:1143-52
Simion, Catalina; Cedano-Prieto, Maria Elvira; Sweeney, Colleen (2014) The LRIG family: enigmatic regulators of growth factor receptor signaling. Endocr Relat Cancer 21:R431-43
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
Frietze, Seth; O'Geen, Henriette; Littlepage, Laurie E et al. (2014) Global analysis of ZNF217 chromatin occupancy in the breast cancer cell genome reveals an association with ERalpha. BMC Genomics 15:520
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
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
Semsri, Suwanna; Krig, Sheryl R; Kotelawala, Lakmal et al. (2011) Inhibitory mechanism of pure curcumin on Wilms' tumor 1 (WT1) gene expression through the PKC? signaling pathway in leukemic K562 cells. FEBS Lett 585:2235-42

Showing the most recent 10 out of 23 publications