Dr. Xin Lin

Regular Member

The University of Texas MD Anderson Cancer Center
Department of Molecular and Cellular Oncology

Research Interests:

• Signal transduction
• Activation of NF-kB family of transcription factors
• Protein phosphorylation
• Lymphocyte activation, development, and differentiation
• Cell proliferation and tumorigenesis

The research in my lab is mainly focused on revealing signal transduction pathways that activate NF-kB family of transcription factors and mitogen-activated protein kinases (MAPKs). NF-kB and MAPKs play critical roles in inflammatory, anti-apoptotic, and immune responses. Revealing of signaling pathways that lead to activation of NF-kB and MAPKs will provide molecular insight for developing therapeutic agents to treat cancer, autoimmune, and inflammatory diseases.

One of projects in my lab is to determine the molecular mechanisms by which NF-kB is activated during T cell activation. Activation of T cells plays a critical role in regulation of immune responses. Dysregulation of T cell activation results in leukemia, autoimmune, and immunodeficiency. This process is induced by the stimulation of T cell receptors (TCR), which leads to activation of multiple transcriptional factors including NF-kB. My lab has taken molecular, cellular, and genetic approaches to study how TCR activates NF-kB. Using a genetic approach, our lab provided first genetic evidence that CARMA1, a caspase recruitment domain (CARD)-containing scaffold protein, is required for TCR-induced NF-kB activation. More recently, we have discovered a novel mechanism of CARMA1-dependent JNK2 activation. Currently, we are extending this line of investigation to leukemia and lymphoma, and have found that there is some mutation occurred in CARMA1 in some types of lymphoma.

The second research area in my lab is to determine the roles of CARMA family members in non-hematopoietic tissues. The CARMA family contains three members. CARMA1 is specifically expressed in hematopoietic tissues, CARMA2 is only expressed in placenta, and CARMA3 is expressed in other non-hematopietic tissues. Using a gene-targeting method, we recently generated CARMA3-deficient mice, and found that CARMA3 mediates G protein-coupled receptor (GPCR)- and receptor tyrosine kinase (RTK)-induced NF-kB activation. Since GPCRs and RTKs play pivotal roles in cell proliferation, survival, and differentiation, we are currently investigating how CARMA3 is involved in these signaling pathways, and its role in cell malignancy.

The third research area in my lab is to determine the biological role of CARD9, a CARD-containing adaptor protein in innate immune responses. By generating CARD9-deficient mice, we recently discovered that CARD9 plays an essential role for innate immune responses against intracellular pathogens. We are currently investigating the molecular mechanism by which CARD9 is involved in innate immune responses against intracellular pathogens.

Students and postdoctoral fellows in my lab will receive training to become independent scientists with the cutting-edge knowledge and technology in molecular and cellular biology, and immunology.

Selected Publications:

Wang, D.; You, Y.; Case, S.M.; Wang, L.; DiStefano, P.S., Nunez, G.; Bertin, J.; Lin, X. (2002) A requirement of CARMA1 in T cell receptor-induced NF-κB activation. Nature Immunology. 3(9): 830-5.

Wang, D.; Matsumoto, R.; You, Y.; Che, T.; Lin, X-Y; Gaffen, SL; Lin, X. (2004) CD3-CD28 costimulation-induced NF-κB activation is mediated by recruitment of PKC-Φ, Bcl10, and IKKβ to the immunological synapse through CARMA1. Mol. Cell. Biol. 24 (1), 164-171.

Che, T.; You, Y.; Wang, D.; Dixit, VM; Tanner, M.J.; Lin, X. (2004) MALT1/Paracaspase is a signaling component downstream of CARMA1 and mediates T cell receptor-induced NF-κB activation. J. Biol. Chem. 279, 15870-15876.

Blonska, M.; You, Y.; Geleziunas, R. Lin, X. (2004) Restoration of NF-κB Activation by tumor necrosis factor-alpha receptor complex-targeted MEKK3 in Receptor-Interacting Protein-deficient cells. Mol. Cell. Biol. 24 (24), 10757-10765.

Matsumoto, R.; Wang, D.; Blonska, M.; Li, H.; Kobayashi, M.; Pappu, B.; Chen, Y.; Wang, D.; Lin, X. (2005) Phosphorylation of CARMA1 plays a critical role in T cell receptor-induced NF-κB activation. Immunity, 23, 1-11, 2005.

Blonska, M.; Shambharkar, P.B.; Kobayashi, M.; Zhang, D.; Sakurai, H.; Su, B.; Lin, X. (2005) TAK1 is recruited into TNFα receptor 1 complex through a RIP-dependent manner and cooperates with MEKK3 leading to NF-κB activation. J. Biol. Chem. 280 (52) 43056-43063, 2005.

Li H; Kobayashi M; Blonska M; You Y; Lin X. (2006) Ubiquitination of RIP is required for TNFα-induced NF-κB activation. J. Biol. Chem. 281 (19) 13636-43.

Pappu, B.; Lin, X. (2006) The role of CARMA1 in splenic B cell development and function. Eur. J. Immunol. 36 (11): 3033-43

Wang, D.; You, Y.; Lin, P.; Xue, L.; Morris, S.; Zeng, H.; Wen, R., Lin, X. (2007) Bcl10 is required for G protein-coupled receptor-induced NF-κB activation. Proc Natl Acad Sci USA (Track II), 104(1): 145-50.

Blonska, M.; Pappu, B.; Li, H.; Matsumoto R.; Su, B.; Wang, D.; Lin, X. (2007) The CARMA1-Bcl10 complex selectively regulates JNK2 in the T cell receptor signaling pathway. Immunity, 26(1): 55-66.

Hsu, MY., Zhang, Y.; You, Y.; Wang, D.; Li, H.; Duramad, O, Qin, X; Dong, C; Lin, X. (2007) CARD9 is required for innate immune responses against intracellular pathogens. Nature Immunology, 8(2): 198-205.

Shambharkar, P.B.; Blonska, M; Pappu, B.P.; Li, H.; You, Y.; Darnay, B.; Lin, X. (2007) Phosphorylation and ubiquitination of IKK complex by two distinct signaling pathways. EMBO J. 26(7): 1794-805.

Grabiner, B.; Lin, P.; Blonska, M.; You, Y.; Wang, D.; Sun, J.; Darnay, BG; Dong, C.; Lin, X. (2007) CARMA3 deficiency abrogates G protein-coupled receptor-induced NF-κB activation. GENES & DEVELPMENT. 21(8): 984-96

Tanner, MJ; Hanel W; Gaffen SL; Lin X (2007) CARMA1 Coiled-coil domain is involved in the oligomerization and subcellular localization of CARMA1, and is required for T cell receptor-induced NF-κB activation. J. Biol. Chem. 282 (23): 17141-7

Sun, J. and Lin, X. (2008) β-arrestin 2 is required for lysophosphatidic acid-induced NF-κB activation. Proc Natl Acad Sci USA (Track II) Nov 4;105 (44):17085-90.

Wu, W., Hsu, YM, Bi, L., Songyang, Z., Lin, X. (2009) CARD9 facilitates microbe-elicited production of reactive oxygen species by regulating the LyGDI-Rac1 complex. Nature Immunology. Nov: 10(11): 1208-14.

Invited reviews:

Lin, X and Wang, D. (2004) The role of CARMA1, Bcl10, and MALT1 in antigen receptor signaling. Seminar in Immunology, 16 (6), 429-435.

Li, H and Lin, X. (2008) Positive and Negative Signaling Components involved in TNFα-induced NF-κB Activation. Cytokine, Jan; 41(1): 1-8.

Blonska, M, and Lin, X (2009) CARMA1-mediated NF-κB and JNK activation in lymphocytes. Immunological Reviews, Mar; 228(1): 199-211.

Additional Publications

Program Affiliations:

Program in Immunology

Program in Cancer Biology