A central paradox in transforming growth factor beta (TGF-?) biology is how the same growth factor can induce such divergent responses as growth stimulation (i.e., mesenchymal cells) and growth inhibition (i.e., epithelial cells)? Considering the pivotal role TGF-? has in a number of normal and pathological conditions, addressing that issue is fundamental if we hope to develop specific intervention strategies. To that end, we have been investigating the general hypothesis that TGF-? signaling is regulated by the coordinate action of membrane proximal and nuclear TGF-? receptor (TGF-?R) activity. In support of that proposal, we provide evidence that (i) FAK (focal adhesion kinase) has an obligate scaffolding function in profibrotic TGF-? signaling whereby it couples the ligand-activated type I TGF-?R to the p85 subunit of PI3K, the most upstream component regulating non-Smad pathways such as PAK2/c-Abl and Akt/mTOR;and (ii) plasma membrane localized type I and type II TGF-?Rs undergo retrograde trafficking and nuclear import following addition of ligand. In this competing renewal we will extend these concepts using a variety of biochemical, genetic, and morphologic approaches. First, we will determine how FAK regulates non-Smad TGF-? signaling through cell type-specific binding with the type I TGF-?R. As the number of effective therapeutic strategies for organ fibrosis is limited, defining this interaction provides potential approaches to uncouple TGF-?'s fibroproliferative actions. Second, the mechanism and targets of TGF-?R trafficking from the cell surface to the nucleus will be defined. These results extend the paradigm whereby the cellular environment directs distinct TGF-? signaling responses. Moreover, as there is significant activity in developing inhibitors to TGF-? action, nuclear TGF-?R activity might impact the efficacy of these treatments.
TGF-? is a protein which can be either helpful or harmful to human health. While its ability to stimulate cell growth is important for normal wound healing, when unchecked the function of many organs can be disrupted by scar (i.e., fibrosis) formation. Conversely, the growth inhibitory actions of TGF-? are critical in preventing cancer. The proposed studies will identify/characterize targets which direct these different activities and can be used to either increase or decrease the response.
|Basal, E; Ayeni, T; Zhang, Q et al. (2016) Patterns of MÃ¼llerian Inhibiting Substance Type II and Candidate Type I Receptors in Epithelial Ovarian Cancer. Curr Mol Med 16:222-31|
|Andrianifahanana, Mahefatiana; Hernandez, Danielle M; Yin, Xueqian et al. (2016) Profibrotic up-regulation of glucose transporter 1 by TGF-Î² involves activation of MEK and mammalian target of rapamycin complex 2 pathways. FASEB J 30:3733-3744|
|Janardhanan, Rajiv; Yang, Binxia; Kilari, Sreenivasulu et al. (2016) The Role of Repeat Administration of Adventitial Delivery of Lentivirus-shRNA-Vegf-A in Arteriovenous Fistula to Prevent Venous Stenosis Formation. J Vasc Interv Radiol 27:576-83|
|Yang, Binxia; Brahmbhatt, Akshaar; Nieves Torres, Evelyn et al. (2016) Tracking and Therapeutic Value of Human Adipose Tissue-derived Mesenchymal Stem Cell Transplantation in Reducing Venous Neointimal Hyperplasia Associated with Arteriovenous Fistula. Radiology 279:513-22|
|Wang, Ying; Cao, Ying; Yamada, Satsuki et al. (2015) Cardiomyopathy and Worsened Ischemic Heart Failure in SM22-Î± Cre-Mediated Neuropilin-1 Null Mice: Dysregulation of PGC1Î± and Mitochondrial Homeostasis. Arterioscler Thromb Vasc Biol 35:1401-12|
|Nallet-Staub, Flore; Yin, Xueqian; Gilbert, CristÃ¨le et al. (2015) Cell density sensing alters TGF-Î² signaling in a cell-type-specific manner, independent from Hippo pathway activation. Dev Cell 32:640-51|
|Wilkes, Mark C; Repellin, Claire E; Kang, Jeong-Han et al. (2015) Sorting nexin 9 differentiates ligand-activated Smad3 from Smad2 for nuclear import and transforming growth factor Î² signaling. Mol Biol Cell 26:3879-91|
|Yang, Binxia; Janardhanan, Rajiv; Vohra, Pawan et al. (2014) Adventitial transduction of lentivirus-shRNA-VEGF-A in arteriovenous fistula reduces venous stenosis formation. Kidney Int 85:289-306|
|Andrianifahanana, Mahefatiana; Wilkes, Mark C; Gupta, Shiv K et al. (2013) Profibrotic TGFÎ² responses require the cooperative action of PDGF and ErbB receptor tyrosine kinases. FASEB J 27:4444-54|
|Yin, Xueqian; Murphy, Stephen J; Wilkes, Mark C et al. (2013) Retromer maintains basolateral distribution of the type II TGF-* receptor via the recycling endosome. Mol Biol Cell 24:2285-98|
Showing the most recent 10 out of 40 publications