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.
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.
|Link, Laura A; Howley, Breege V; Hussey, George S et al. (2016) PCBP1/HNRNP E1 Protects Chromosomal Integrity by Translational Regulation of CDC27. Mol Cancer Res 14:634-46|
|Howley, B V; Hussey, G S; Link, L A et al. (2016) Translational regulation of inhibin Î²A by TGFÎ² via the RNA-binding protein hnRNP E1 enhances the invasiveness of epithelial-to-mesenchymal transitioned cells. Oncogene 35:1725-35|
|Brown, Andrew S; Mohanty, Bidyut K; Howe, Philip H (2015) Computational Identification of Post Translational Modification Regulated RNA Binding Protein Motifs. PLoS One 10:e0137696|
|Hussey, George S; Link, Laura A; Brown, Andrew S et al. (2012) Establishment of a TGFÎ²-induced post-transcriptional EMT gene signature. PLoS One 7:e52624|
|Jiang, Yong; He, Xi; Howe, Philip H (2012) Disabled-2 (Dab2) inhibits Wnt/Î²-catenin signalling by binding LRP6 and promoting its internalization through clathrin. EMBO J 31:2336-49|
|Hussey, George S; Chaudhury, Arindam; Dawson, Andrea E et al. (2011) Identification of an mRNP complex regulating tumorigenesis at the translational elongation step. Mol Cell 41:419-31|
|Chaudhury, Arindam; Hussey, George S; Howe, Philip H (2011) 3'-UTR-mediated post-transcriptional regulation of cancer metastasis: beginning at the end. RNA Biol 8:595-9|
|Chaudhury, Arindam; Hussey, George S; Ray, Partho S et al. (2010) TGF-beta-mediated phosphorylation of hnRNP E1 induces EMT via transcript-selective translational induction of Dab2 and ILEI. Nat Cell Biol 12:286-93|
|Chaudhury, Arindam; Chander, Praveen; Howe, Philip H (2010) Heterogeneous nuclear ribonucleoproteins (hnRNPs) in cellular processes: Focus on hnRNP E1's multifunctional regulatory roles. RNA 16:1449-62|
|Jiang, Y; Luo, W; Howe, P H (2009) Dab2 stabilizes Axin and attenuates Wnt/beta-catenin signaling by preventing protein phosphatase 1 (PP1)-Axin interactions. Oncogene 28:2999-3007|
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