The T-cell factor (TCF) family plays key roles in the control of gene expression in response to secreted Wnt proteins. Wnt pathways operate to modulate cell proliferation, migratory behavior, cell fate determination and cell death. This proposal aims to study the regulation of TCF3, a transcriptional repressor which has been implicated in Wnt signaling during cell differentiation and tumorigenesis. Our preliminary experiments in Xenopus ectoderm and mammalian cells identified a specific post-translational change in TCF3 protein mobility that correlates with Wnt target gene activation. This effect has been demonstrated to involve homeodomain-interacting protein kinase (HIPK), leading to a hypothesis that Wnt proteins act via HIPK2 and TCF3 to regulate their transcriptional targets. This hypothesis will be tested in mammalian cells and Xenopus eggs, in which biochemical and cell biological approaches can be combined with rapid functional analysis of underlying mechanisms. To investigate roles of TCF3 postranslational modification for Wnt-dependent activation of target genes, non- phosphorylatable and phosphomimetic TCF3 mutant proteins will be compared in morphological and molecular assays. Other experiments will elucidate how Wnt signals activate HIPK and trigger TCF3 post-translational modifications that are critical for target gene regulation. These studies will help characterize basic signaling networks normally leading to cell proliferation and differentiation, but which are misregulated during disease. Given the association of Wnt pathways with cancer, the knowledge of how TCF3 is regulated will serve as a basis for new drug screens and should lead to the development of crucial therapeutic strategies.

Public Health Relevance

This application concerns the function of TCF3, a Wnt-dependent transcriptional repressor that is essential for the regulation of cell proliferation. Since Wnt pathways have been found activated in a variety of tumors, the proposed studies are highly relevant to human cancer.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM096959-03
Application #
8449675
Study Section
Development - 2 Study Section (DEV2)
Program Officer
Gaillard, Shawn R
Project Start
2011-04-01
Project End
2015-03-31
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
3
Fiscal Year
2013
Total Cost
$399,570
Indirect Cost
$163,836
Name
Icahn School of Medicine at Mount Sinai
Department
Biology
Type
Schools of Medicine
DUNS #
078861598
City
New York
State
NY
Country
United States
Zip Code
10029
Sokol, Sergei Y (2011) Wnt signaling through T-cell factor phosphorylation. Cell Res 21:1002-12
Sokol, Sergei Y (2011) Maintaining embryonic stem cell pluripotency with Wnt signaling. Development 138:4341-50
Hikasa, Hiroki; Sokol, Sergei Y (2011) Phosphorylation of TCF proteins by homeodomain-interacting protein kinase 2. J Biol Chem 286:12093-100