Penn Veterinary Medicine | University of Pennsylvania

Description of Research Expertise

Research Interests
Aberrations of protein ubiquitination and degradation in cancer.

Key words: ubiquitin, ligase, proteolysis, cancer, cytokine, signal transduction.

Description of Research
Protein ubiquitination and degradation have emerged as important mechanisms in regulating cell growth and survival that play a key role in cancer. The long-term objective our laboratory is to identify the aberrations in ubiquitination of regulatory proteins that contribute to cell transformation and tumor progression and determine the usefulness of specific mediators of ubiquitination as potential targets for anti-cancer therapy. Our current focus is on the disregulated proteolysis of cytokine and hormone receptors in human malignant melanomas and breast cancers. For our studies, we employ various approaches and methods of molecular and cellular biology, biochemistry and mammalian genetics.

Main research areas:

1.Proteolysis of the interferon alpha receptor. 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. We recently found that ligand-dependent down regulation of this receptor depends on its phosphorylation and ubiquitination by the beta-Trcp/HOS E3 ubiquitin ligase. This down regulation is accelerated in some human tumors including malignant melanomas. We are determined to understand the molecular mechanisms of IFNalpha receptor phosphorylation, ubiquitination, endocytosis and degradation as well as aberrations of these processes in cancers and the role of IFN receptor stability in the anti-tumorigenic effects of IFNalpha.

2. Proteolysis of the prolactin receptor that mediate cellular responses to hormone/cytokine prolactin, which is crucial for survival of human breast epithelial cells. Whereas degradation of prolactin receptor also involves specific phosphorylation, beta-Trcp-dependent ubiquitination and endocytosis, human breast cancer cells gain advantage in prolactin signaling by inhibiting the phosphorylation and degradation of its receptor. Investigation of the mechanisms of this inhibition and the role of increased stability of prolactin receptor in pathogenesis of breast cancer is currently underway.

3. Identification of novel substrates for beta-Trcp E3 ubiquitin ligase and delineation of the mechanisms that regulate the activities of this ligase. Beta-Trcp levels and activities are often up-regulated in human cancers to ensue rapid proteolysis of proteins that negatively affect cell growth and survival (such as IkappaB, Emi1, etc). Conversely, the inhibition of beta-Trcp impairs growth and survival of human cancer cells. The ongoing delineation of the mechanisms regulating beta-Trcp activities and identification of its substrates may pave the road to targeting beta-Trcp for the therapeutic purposes.

Rotation Projects for 2006-2007
Lab rotation projects are available in every main research area.

Lab personnel:
• Serge Y. Fuchs, M.D., Ph.D. P.I.
• Suresh Kumar K.G., Ph.D., Research Associate
• Jianghuai Liu, Ph.D., Postdoctoral Fellow
• Alex Plotnikov, Ph.D., Postdoctoral Fellow
• Gayathri Swaminathan, Ph.D., Postdoctoral Fellow

Selected Publications

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(7): 3165-72, Apr 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(1): 72-83, Jan 2009.

Frank Stuart J, Fuchs Serge Y: Modulation of growth hormone receptor abundance and function: roles for the ubiquitin-proteasome system. Biochimica et biophysica acta 1782(12): 785-94, Dec 2008.

HuangFu Wei-Chun, Liu Jianghuai, Harty Ronald N, Fuchs Serge Y: Cigarette smoking products suppress anti-viral effects of Type I interferon via phosphorylation-dependent downregulation of its receptor. FEBS letters 582(21-22): 3206-10, Sep 2008.

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(17): 5275-87, Sep 2008.

Kumar K G Suresh, Varghese Bentley, Banerjee Anamika, Baker Darren P, Constantinescu Stefan N, Pellegrini Sandra, Fuchs Serge Y: Basal ubiquitin-independent internalization of interferon alpha receptor is prevented by Tyk2-mediated masking of a linear endocytic motif. The Journal of biological chemistry 283(27): 18566-72, Jul 2008.

Plotnikov Alexander, Li Ying, Tran Thai H, Tang Weigang, Palazzo Juan P, Rui Hallgeir, Fuchs Serge Y: Oncogene-mediated inhibition of glycogen synthase kinase 3 beta impairs degradation of prolactin receptor. Cancer research 68(5): 1354-61, Mar 2008.

Liu Jianghuai, Plotnikov Alexander, Banerjee Anamika, Suresh Kumar K G, Ragimbeau Josiane, Marijanovic Zrinka, Baker Darren P, Pellegrini Sandra, Fuchs Serge Y: Ligand-independent pathway that controls stability of interferon alpha receptor. Biochemical and biophysical research communications 367(2): 388-93, Mar 2008.

Swaminathan Gayathri, Varghese Bentley, Thangavel Chellappagounder, Carbone Christopher J, Plotnikov Alexander, Kumar K G Suresh, Jablonski Elizabeth M, Clevenger Charles V, Goffin Vincent, Deng Luqin, Frank Stuart J, Fuchs Serge Y: Prolactin stimulates ubiquitination, initial internalization, and degradation of its receptor via catalytic activation of Janus kinase 2. The Journal of endocrinology 196(2): R1-7, Feb 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(5): 935-50, Dec 2007.