Transforming Growth Factor Beta Receptor type 3 signals through p38 MAP kinase pathway to induce apoptosis in conventional renal cell carcinoma The type III TGFbeta receptor (TβRIII) has an established function as a TGFbeta (TGFβ) superfamily co-receptor and an emerging role in mediating signaling through its cytoplasmic domain. We evaluated the mechanism of TβRIII induced apoptosis in conventional renal cell carcinoma (cRCC). In previously described localized cRCC tumor model (UMRC6, express TβRI, TβRII), metastatic RCC tumor model (UMRC3, express TβR1), and primary cRCC cell cultures from index tumors, nodal and systemic metastases, TβR3 expression was manipulated with Adenoviral gene vector (Ad-TβR3) delivery system. Signaling through TGFβ pathway was assessed by SMAD 2/3 and p38 MAP kinase phosphorylation state. Induction of apoptosis was evaluated by FITC-labeled annexin-V and propidium iodide FACS analysis. Infection with Ad-TβR3, consistently resulted in induction of apoptosis in UMRC3 cell lines, which lack TβR2, in UMRC6 cell lines stably transfected with a dominant negative TβR2, and in primary cRCC cell cultures from index tumors, nodal and systemic metastases. Lack of SMAD signaling was confirmed in these models with western blotting and SMAD reporter assays. Induction of apoptosis through Ad-TβR3 was not dependent on circulating levels of TGFβ, or presence of functional extracellular domain of TβR3 receptor. Increased signaling through p38 MAP kinase pathway was observed in all cell lines after infection with Ad-TβR3 and extracellular domain deleted Ad-TβR3, while Ad-TβR3 mediated apoptosis of cRCC cell lines was completely reversed by pre-treating cells with a selective p38 MAP kinase inhibitor SB202190. Challenging the notion of TβR3 as a non-signaling receptor, we have identified SMAD and TβR2 independent TβR3 signaling through p38 MAP kinase pathway. This novel pathway may be an important apoptotic mechanism in RCC. Molecular Portraits of Epithelial, Mesenchymal, and Hybrid States in Lung Adenocarcinoma and Their Relevance to Survival Chronic Inflammation Induces a Novel Epigenetic Program That Is Conserved in Intestinal Adenomas and in Colorectal Cancer Source.