Aberrations of cytokine receptors ubiquitination and degradation in cancer, inflammation and autoimmune diseases
Key words: interferon, receptor, ubiquitin, ligase, cancer, inflammation, cytokine, signal transduction
Description of Research
Protein mediators of intercellular signaling (cytokines and growth factors) ensure a collective behavior of cells within a tissue via binding to their cognate receptors and triggering complex programs of signal transduction and transcriptional regulation. Responsiveness of cells to these protein regulators depend on the cell surface levels of receptors that rapidly undergo ubiquitination and downregulation in response to ligands as well as other intra- and extracellular stimuli. These signaling processes leading to cell de-sensitization collectively termed “ELIMINATIVE SIGNALING” are the focus of our studies. The long-term objective our laboratory is to identify the aberrations in eliminative signaling of cytokine/growth factor receptors that are critical to development of cancers, and responses to infections and autoimmune processes. For our studies, we employ various approaches and methods of molecular and cellular biology, biochemistry and mammalian genetics.
Main research area: Eliminative signaling by interferons (IFN) and proteolysis of the interferon alpha receptor (IFNAR). This receptor plays an essential role in anti-tumorigenic, anti-viral and immunomodulatory effects of Type I IFN, which are often used in therapy of cancers, chronic viral infections and multiple sclerosis. Enzymatic regulators of IFNAR fate include specific protein kinases, phosphatases, E3 ubiquititin ligases and de-ubiquitinating enzymes. We are determined to identify and characterize these regulators and to use this knowledge for stabilization of IFNAR and increasing the efficacy of IFN against cancers and chronic viral infections. Conversely, we search for stimulators of IFNAR downregulation to prevent harmful effects of IFN in pathogenesis of autoimmune diseases.
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