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.
Plotnikov Alexandr, Varghese Bentley, Tran Thai H, Liu Chengbao, Rui Hallgeir, Fuchs Serge Y Impaired turnover of prolactin receptor contributes to transformation of human breast cells. Cancer research 69: 3165-72, 2009.Liu Jianghuai, HuangFu Wei-Chun, Kumar K G Suresh, Qian Juan, Casey James P, Hamanaka Robert B, Grigoriadou Christina, Aldabe Rafael, Diehl J Alan, Fuchs Serge Y Virus-induced unfolded protein response attenuates antiviral defenses via phosphorylation-dependent degradation of the type I interferon receptor. Cell host & microbe 5: 72-83, 2009.Varghese Bentley, Barriere Herve, Carbone Christopher J, Banerjee Anamika, Swaminathan Gayathri, Plotnikov Alexander, Xu Ping, Peng Junmin, Goffin Vincent, Lukacs Gergely L, Fuchs Serge Y Polyubiquitination of prolactin receptor stimulates its internalization, postinternalization sorting, and degradation via the lysosomal pathway. Molecular and cellular biology 28: 5275-87, 2008.Kumar K G Suresh, Barriere Hervé, Carbone Christopher J, Liu Jianghuai, Swaminathan Gayathri, Xu Ping, Li Ying, Baker Darren P, Peng Junmin, Lukacs Gergely L, Fuchs Serge Y Site-specific ubiquitination exposes a linear motif to promote interferon-alpha receptor endocytosis. The Journal of cell biology 179: 935-50, 2007.Zheng Hui, Qian Juan, Carbone Christopher J, Leu N Adrian, Baker Darren P, Fuchs Serge Y Vascular endothelial growth factor-induced elimination of the type 1 interferon receptor is required for efficient angiogenesis. Blood 118: 4003-6, 2011.Bhattacharya Sabyasachi, Zheng Hui, Tzimas Christos, Carroll Martin, Baker Darren P, Fuchs Serge Y Bcr-abl signals to desensitize chronic myeloid leukemia cells to IFNa via accelerating the degradation of its receptor. Blood 118: 4179-87, 2011.Qian Juan, Zheng Hui, Huangfu Wei-Chun, Liu Jianghuai, Carbone Christopher J, Leu N Adrian, Baker Darren P, Fuchs Serge Y Pathogen recognition receptor signaling accelerates phosphorylation-dependent degradation of IFNAR1. PLoS pathogens 7: e1002065, 2011.Huangfu W-C, Qian J, Liu C, Liu J, Lokshin A E, Baker D P, Rui H, Fuchs S Y Inflammatory signaling compromises cell responses to interferon alpha. Oncogene 31: 161-72, 2012.Zheng Hui, Qian Juan, Varghese Bentley, Baker Darren P, Fuchs Serge Ligand-stimulated downregulation of the alpha interferon receptor: role of protein kinase D2. Molecular and cellular biology 31: 710-20, 2011.Liu Jianghuai, Carvalho Lucas P, Bhattacharya Sabyasachi, Carbone Christopher J, Kumar K G Suresh, Leu N Adrian, Yau Peter M, Donald Robert G K, Weiss Mitchell J, Baker Darren P, McLaughlin K John, Scott Phillip, Fuchs Serge Y Mammalian casein kinase 1alpha and its leishmanial ortholog regulate stability of IFNAR1 and type I interferon signaling. Molecular and cellular biology 29: 6401-12, 2009.