Regulator of G protein signaling RGS3 is a GTPase-activating protein (GAP) that binds G-alpha subunits of heterotrimeric G proteins and accelerates their GTPase activity. We and others have shown that through this mechanism, RGS3 regulates the signaling of Gq- and Gi-coupled receptors to angiotensin II, endothelin-1, carbachol, gonadotropin-releasing hormone and sphingosine-1 phosphate. Our new data suggest that a) RGS3 interacts with the transducers of TGF-2 signaling, Smad transcription factors that were previously thought to be unrelated to G protein / RGS axis;b) RGS3 inhibits Smad-mediated gene transcription;and c) RGS3 is abundant in T-lymphocytes and its expression in T cells is further induced by TGF-2 treatment. In T cells, G protein signaling is associated with migration towards various chemokines, whereas TGF-2 signaling controls proliferation and differentiation of T cells at multiple levels. The function of endogenous RGS3 has not been investigated in T cells. Based on our preliminary data, we hypothesize that (i) RGS3 is a multifunctional protein that, in addition to regulating G protein signaling, also modulates the signaling of TGF-2, and (ii) endogenous RGS3 controls T cell migration, proliferation and differentiation through the regulation of both G protein- and TGF-2 signaling. To test these hypotheses, we propose three specific aims: (i) investigate the molecular nature and functional consequences of RGS3 / Smad interaction by overexpression of RGS3 and its mutants, (ii) investigate the regulation of G protein- and TGF-2 signaling by endogenous RGS3 in EL4 T thymoma cell line;and (iii) examine how RGS3 controls T cell migration, proliferation and differentiation in response to TGF-2 and chemokines, using T cells from RGS3-knockout mouse. The fundamental significance of this study relates to a potential discovery of a novel, non-canonical function of RGS3 as a regulator of TGF-2 signaling. The practical importance of this study relates to understanding the diseases associated with abnormal immune responses of T cell.
Appropriate function of T lymphocytes is critical for the adaptive immunity, whereas abnormal function of T cells leads to autoimmune and inflammatory diseases such as asthma, multiple sclerosis, rheumatoid arthritis, type I diabetes and others. Therefore, defining the molecular mechanisms of T cell activation and differentiation may lead to a better understanding the pathogenesis of these diseases.
|Orlov, Sergei N; Koltsova, Svetlana V; Kapilevich, Leonid V et al. (2015) NKCC1 and NKCC2: The pathogenetic role of cation-chloride cotransporters in hypertension. Genes Dis 2:186-196|
|Kach, Jacob; Sandbo, Nathan; La, Jennifer et al. (2014) Antifibrotic effects of noscapine through activation of prostaglandin E2 receptors and protein kinase A. J Biol Chem 289:7505-13|
|Kach, Jacob; Sandbo, Nathan; Sethakorn, Nan et al. (2013) Regulation of myofibroblast differentiation and bleomycin-induced pulmonary fibrosis by adrenomedullin. Am J Physiol Lung Cell Mol Physiol 304:L757-64|
|Sethakorn, Nan; Dulin, Nickolai O (2013) RGS expression in cancer: oncomining the cancer microarray data. J Recept Signal Transduct Res 33:166-71|
|Sandbo, Nathan; Ngam, Caitlyn; Torr, Elizabeth et al. (2013) Control of myofibroblast differentiation by microtubule dynamics through a regulated localization of mDia2. J Biol Chem 288:15466-73|
|Williams, Jesse W; Yau, Douglas; Sethakorn, Nan et al. (2013) RGS3 controls T lymphocyte migration in a model of Th2-mediated airway inflammation. Am J Physiol Lung Cell Mol Physiol 305:L693-701|
|Kach, Jacob; Sethakorn, Nan; Dulin, Nickolai O (2012) A finer tuning of G-protein signaling through regulated control of RGS proteins. Am J Physiol Heart Circ Physiol 303:H19-35|
|Chakir, Khalid; Depry, Charlene; Dimaano, Veronica L et al. (2011) Galphas-biased beta2-adrenergic receptor signaling from restoring synchronous contraction in the failing heart. Sci Transl Med 3:100ra88|
|Sandbo, Nathan; Dulin, Nickolai (2011) Actin cytoskeleton in myofibroblast differentiation: ultrastructure defining form and driving function. Transl Res 158:181-96|
|Sandbo, Nathan; Lau, Andrew; Kach, Jacob et al. (2011) Delayed stress fiber formation mediates pulmonary myofibroblast differentiation in response to TGF-?. Am J Physiol Lung Cell Mol Physiol 301:L656-66|
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