The ErbB family of receptor tyrosine kinases mediates the development and maintenance of a variety of tissue types, including cardiac and neural tissues, and receptor overexpression or aberrant activation can lead to the formation and progression of many solid tumors types. While the mechanisms by which RTKs regulate cellular growth properties have received much attention over the years, mechanisms modulating the efficiency of RTK signaling remain largely unexplored. The efficiency of ErbB response to ligand binding must be very tightly regulated to ensure sufficient signaling activity to mediate developmental processes, while preventing the hyper-signaling that could lead to cancer. The overall objective of this project is to understand the mechanisms by which receptor modulation pathways operate. Two unrelated ErbB modulator proteins, Nrdp1 and Muc4, influence the ability of the ErbB2/ErbB3 heterodimeric receptor complex to respond to the growth factor NRG1 by influencing receptor trafficking and localization. Nrdp1 is an E3 ubiquitin ligase that suppresses NRG1 signaling by mediating the ubiquitination and degradation of ErbB3.
Specific Aim 1 of the proposed studies examines the molecular mechanisms by which Nrdp1 is regulated, focusing on the activities and phosphorylation of two deubiquitinating enzymes that act in the Nrdp1 pathway. Muc4 is a membrane mucin that physically interacts with ErbB receptors and potentiates the response of the ErbB2/ErbB3 complex to NRG1. This protein inhibits receptor internalization, resulting in the net translocation of receptors from intracellular compartments to the surface of tumor cells.
Specific Aim 2 examines the molecular mechanisms by which Muc4 alters receptor trafficking and localization.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
3R01GM068994-12S1
Application #
8188461
Study Section
Molecular Oncogenesis Study Section (MONC)
Program Officer
Maas, Stefan
Project Start
1997-12-31
Project End
2012-08-31
Budget Start
2010-09-01
Budget End
2012-08-31
Support Year
12
Fiscal Year
2011
Total Cost
$57,169
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
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Krig, Sheryl R; Frietze, Seth; Simion, Catalina et al. (2011) Lrig1 is an estrogen-regulated growth suppressor and correlates with longer relapse-free survival in ERα-positive breast cancer. Mol Cancer Res 9:1406-17
Carraway 3rd, Kermit L (2010) E3 ubiquitin ligases in ErbB receptor quantity control. Semin Cell Dev Biol 21:936-43
Chen, Liqun; Siddiqui, Salma; Bose, Swagata et al. (2010) Nrdp1-mediated regulation of ErbB3 expression by the androgen receptor in androgen-dependent but not castrate-resistant prostate cancer cells. Cancer Res 70:5994-6003
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Fry, William H D; Kotelawala, Lakmal; Sweeney, Colleen et al. (2009) Mechanisms of ErbB receptor negative regulation and relevance in cancer. Exp Cell Res 315:697-706
Workman, Heather C; Sweeney, Colleen; Carraway 3rd, Kermit L (2009) The membrane mucin Muc4 inhibits apoptosis induced by multiple insults via ErbB2-dependent and ErbB2-independent mechanisms. Cancer Res 69:2845-52
Workman, Heather C; Miller, Jamie K; Ingalla, Ellen Q et al. (2009) The membrane mucin MUC4 is elevated in breast tumor lymph node metastases relative to matched primary tumors and confers aggressive properties to breast cancer cells. Breast Cancer Res 11:R70

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