Breast Cancer Research Program (BCRP) - Predoctoral Traineeship - Elucidating the Role of the Type III Transforming Growth Factor-beta Receptor in Bone Morphogenetic Signaling in Breast Cancer
Annual summary rept. 1 Mar 2005-29 Feb 2008
DUKE UNIV DURHAM NC
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We have identified and characterized the Transforming Growth Factor-betaTGF-beta Type III ReceptorTbetaRIII as a cell surface receptor for the Bone Morphogenetic ProteinsBMP. This report demonstrates that loss of TbetaRIII results in alterations in intracellular signaling by BMP specifically phosphorylation of the intracellular effector Smad1. We determine that the effect of loss of TbetaRIII on Smad1 phosphorylation is cell-type specific. We have also determined that TbetaRIII facilitates internalization of ALK6 in the presence of beta-arrestin2 beta-arr2. Here we demonstrate that TbetaRIII and beta-arr2 together dramatically enhance the immunoprecipitation of a complex containing ALK6. We also show that this complex of TbetaRIII beta-arr2 and ALK6 dramatically increase BMP-2-induced transcriptional responses. We have begun to apply this molecular data to elucidate the role of TbetaRIII and BMP proteins in carcinogenesis to better understand their potential role in breast cancer. Recent data demonstrates an increase in expression of BMP ligands by a number of cancer cell types. Here we demonstrate that BMP treatment decreases expression of TbetaRIII and induces an epithelial to mesenchymal transition EMT in pancreatic cancer suggesting a mechanism by which TbetaRIII is lost during carcinogenesis and leads to an increase in invasiveness of cancer cells.
- Medicine and Medical Research
- Organic Chemistry