Characterization of Odin, a Novel Inhibitory Molecule, in EGF Receptor Signaling

Project: Research project

Project Details

Description

PUBLIC ABSTRACT

Dysregulated tyrosine kinase activity is implicated in a large number of human cancers. Several members of the epidermal growth factor receptor (EGFR) family are amplified and overexpressed in human tumors and abrogation of their activity can lead to improved prognosis and survival. Although the mechanism underlying the mitogenic pathways initiated by receptor tyrosine kinases are quite well understood, little is known about how these proliferative signals are shut off. In a proteomic screen for molecules in the EGFR pathway, we identified Odin, a novel tyrosine-phosphorylated adapter protein containing PTB, Ankyrin and SAM domains. We have demonstrated that overexpression of Odin leads to inhibition of growth factor-induced signaling and proliferation in fibroblasts. RNAi-based knockdown of the Odin ortholog in C. elegans leads to sterility, indicating the importance of this evolutionary conserved molecule. In preliminary studies, we have shown that Odin associates with several proteins in an EGF-inducible fashion, we have also identified, using a yeast 2-hybrid screen, Grb2, as a protein that interacts with Odin. Database searches also reveal that Odin expression is significantly lower in two very common cancers, lung and breast cancers, than in their normal tissue. Based on this data, we hypothesize that Odin acts as a negative regulator of growth factor receptor signaling by binding to Grb2 and disrupting the Grb2/Sos/Ras complex. Further, Odin plays a role in transformation of cells by activated kinases and in mammary gland development and tumor formation. We will test this hypothesis by (1) defining the role of the Odin-Grb2 interaction and by identifying functional domains in Odin critical for its inhibitory activity (2) identifying proteins associated with Odin using a proteomic approach, (3) using Odin knockout mice to study the role of Odin in normal mammary gland development and tumorigenesis. The significance of this proposal is that these studies will define the precise interactions involved in Odin-mediated downregulation of growth factor induced signaling, and elucidate the in vivo relevance of Odin in normal breast cancer development and in tumorigenesis. The proposal capitalizes on the expertise of the Principal Investigator in proteomics and molecular biology and applies it to the study of a poorly studied negative regulatory component of a pathway commonly disrupted in human cancers. A detailed understanding of such inhibitory mechanisms will provide novel strategies for targeting intracellular signaling molecules in the treatment of human breast cancers.

StatusFinished
Effective start/end date1/1/0412/31/04

Funding

  • U.S. Department of Defense: $87,918.00

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