Regulation of Canonical Wnt Signaling by the beta-Catenin Antagonist Chibby

State University New York Stony Brook, Stony Brook NY

Investigators

Abstract

DESCRIPTION (provided by applicant): The canonical Wnt/[unreadable]-catenin signaling pathway regulates virtually all aspects of embryonic development. More recently, dysregulation of this signaling cascade has been linked to a range of human diseases, most notably cancer. Activation of this pathway results in stabilization of the central component [unreadable]-catenin in the cytoplasm, and [unreadable]-catenin then translocates into the nucleus where it forms a complex with the T-cell factor/lymphoid enhancer factor (Tcf/Lef) family of transcription factors to stimulate target gene expression. The investigator previously reported an evolutionarily conserved molecule Chibby (Cby) that directly binds to [unreadable]-catenin and inhibits its transcriptional activation potential. Inhibition of Drosophila Cby by RNAi results in embryonic lethality and Cby-null mice die embryonically or perinatally due to hyperactivation of [unreadable]-catenin signaling, highlighting its biological importance during animal development. Nonetheless, little is known about the cellular and molecular functions of Cby. Recently, the investigator found that Cby interacts with itself, and this self-association might be crucial for its biological function. Therefore, she proposes to further molecularly dissect the Cby-Cby interaction. Moreover, she recently isolated 14-3-3 adaptor proteins as novel Cby interactors through affinity purification/mass spectrometry. The investigator plans to characterize Cby-14- 3-3 interactions in detail and ultimately elucidate how 14-3-3 binding to Cby influences Wnt/[unreadable]-catenin signaling. Through these studies, she hopes to reveal a novel mechanism controlling the dynamic nucleo-cytoplasmic trafficking of [unreadable]-catenin. Hence, the project is most likely to yield insight into physiological mechanisms governing normal embryonic development. In order to achieve these goals, the following aims are proposed: Specific Aim 1 will define domains/amino acids essential for the Cby-Cby interaction, and evaluate their functional importance;Specific Aim 2 will characterize Cby-14-3-3 interactions, and examine whether binding of 14-3-3 to Cby modulates Wnt/[unreadable]-catenin signaling. PUBLIC HEALTH RELEVANCE: The Wnt [unreadable]-catenin pathway plays crucial roles during embryonic development. Chibby (Cby) is a conserved core component that binds to [unreadable]-catenin and inhibits its transcriptional activation potential. The investigator has found that Cby interacts with itself and 14-3-3 adaptor proteins. Thus, this project is focused on molecular and functional characterization of these protein-protein interactions to gain insight into how [unreadable]-catenin signaling activity might be regulated during development.