Research in the Howe laboratory is focused on understanding the signaling pathways activated by transforming growth factor ß1 (TGFß1), interleukin-like EMT inducer (ILEI) and Wnt in cellular models of differentiation and cancer. One major area of interest is a recently identified signaling pathway whereby TGFß regulates epithelial-mesenchymal transitions (EMT) and metastasis through a post-transcriptional mechanism involving the regulation of an RNA binding protein, heterogeneous ribonucleoprotein E1 (hnRNP E1). We are focused on how TGFß regulation of hnRNP E1 phosphorylation not only regulates translational silencing of select mRNAs involved in EMT/metastasis but also of lncRNAs that may also contribute to tumor progression. Candidate mRNA targets and lncRNAs are actively being pursued and one mRNA target in particular, the cytokine ILEI, has become a major focus of the laboratory. Aside from its known role in EMT, relatively little is known regarding ILEI. We have identified ILEI as a potent stem factor in breast epithelium and are actively investigating the molecular mechanisms through which it mediates its progenitor effects.
In another focus area we are investigating the role of the adaptor molecule, disabled-2 (Dab2), as a mediator of the cross-talk between the TGFß and Wnt signaling pathways. We have shown that the tumor suppressor functions of Dab2 are mediated thru its attenuation of canonical Wnt/ß-catenin signaling by selectively recruiting the Wnt co-receptor LRP6 to the clathrin-dependent endocytic route, thereby sequestering it from caveolin-mediated endocytosis and signaling. TGFß levels in cells and tissues regulates Dab2 expression and thereby regulates, thru Dab2, Wnt signaling. We are currently investigating this cross-talk in the developing zebrafish and in animal tumor models. We have also made the recent observation that Dab2 regulates TGFß-induced apoptosis and autophagy. We have shown that mechanistically Dab2 serves as a molecular switch to control whether cells undergo apoptosis or autophagy in response to TGFß, and significantly this switch may be underlie chemosensitivity and acquired-resistance during tumorigenesis.