The endocytic adaptor molecule disabled-2 (Dab2) has been assigned the label of tumor suppressor because its expression level in many tumors and tumor-derived cell lines is aberrantly low, and its re-expression in these lines results in cel cycle arrest and a decreased rate of proliferation. In addition, Dab2 has been demonstrated to play a critical role in cellular differentiation and lineage commitment. Its function is essential during not only megakaryocytic differentiation and differentiation of embryonic stem cells into primitive endoderm4, but also during TGF?-mediated epithelial-mesenchymal transdifferentiation (EMT). The molecular basis for this apparent tumor suppressor and differentiation function of Dab2 is unknown. We hypothesize that Dab2 mediates its growth suppressor and differentiation effects by mediating cross-talk between the TGF? and Wnt signaling pathways. It is our contention (supported by our published and preliminary data) that in undifferentiated cells, the expression of Dab2 is low and cells are responsive to Wnt, and upon differentiation and induction of Dab2, cells become refractory to Wnt signaling. Thus, in differentiated cells, we propose that Dab2 maintains the differentiated state and restrains proliferation through its negative regulation of Wnt signaling. Loss of Dab2, as observed in many tumor cel lines or in epithelial cells having undergone the mesenchymal transition, leads to sustained Wnt signaling and tumorigenesis. The goal of this proposal is to investigate the molecular basis for Dab2's inhibitory effects on Wnt signaling, specifically effects on LRP6 receptor internalization, and to investigate the molecular mechanism leading to downregulation of Dab2 that occurs following EMT and acquisition of the mesenchymal state.

Public Health Relevance

Context-specific signaling by TGF? is of great significance to our development of anti-cancer strategies and therapeutics. Understanding how cell-type specific phenotypes are elicited by TGF? is vital to the design of therapeutics that target its tumor promoter, and not its tumor suppressor functions. The successful pursuit of the studies proposed herein will elucidate the molecular mechanism through which TGF? switches from a tumor suppressor to a tumor promoter in a context-specific manner and should provide insight aimed at modulation of its proliferative and tumor promoter function.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
2R01CA055536-22A1
Application #
8355036
Study Section
Tumor Cell Biology Study Section (TCB)
Program Officer
Salnikow, Konstantin
Project Start
1992-02-01
Project End
2017-05-31
Budget Start
2012-08-01
Budget End
2013-05-31
Support Year
22
Fiscal Year
2012
Total Cost
$294,196
Indirect Cost
$94,741
Name
Medical University of South Carolina
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
183710748
City
Charleston
State
SC
Country
United States
Zip Code
29425