Rheumatic Diseases Research Core
Stem Cell Center, Yale: Signal Transduction and Cell Growth
The research in my laboratory focuses on the biology of signal transduction mediated by the intracellular protein kinase network such as the mitogen-activated protein kinase (MAPK) cascades and the mammalian target of rapamycine (mTOR) pathway in immune responses and in blood vessel function/development. We study the genes that encode either the serine/threonine kinases or their regulators in the kinase pathways. Our studies have revealed the roles of these kinase pathways in transducing various receptor signals and in regulating cell growth, differentiation, and apoptosis.
Extensive Research Description
The research in my laboratory focuses on the biology of signal transduction mediated by the intracellular protein kinase networks. We study the mitogen-activated protein kinase (MAPK) pathway and the mammalian target of rapamycine (mTOR) pathway. We wish to understand how these intracellular kinase pathways are utilized and regulated by immune system and cardiovascular system. Specifically, we want to reveal their specificity and physiological function in immune responses and in cardiovascular development and function.
We are also working to elucidate the underlying molecular mechanisms by which the kinase pathway-mediated receptor signaling regulates immune cell development, differentiation and effector function, as well as angiogenic signaling for cardiovascular development. Furthermore, we want to study the immune and inflammatory responses in the cardiovascular system and to determine how the MAPK pathway and the mTOR pathway are involved in these processes in physiological and pathological conditions.
To address the questions describe above, we have studied two Ser/Thr protein kinase molecules called MEKK2 and MEKK3 belonging to the MAP3K family in the MAPK pathway, and an adaptor molecule called Sin1, in the mTOR pathway. Thus far, my laboratory has generated knockout mice (both germline and conditional knockout) for these molecules to study their roles in the immune and cardiovascular systems. We have found that both MEKK2 and MEKK3 are key signaling molecules in the immune cells and endothelial cells, are required for multiple receptor-generated signals, and are also required for cellular stress responses.
We also demonstrated that Sin1 is a key regulator of the mTOR complex 2 (mTORC2) and is essential for Akt HM and TM site phosphorylation. Sin1-mTORC2 may also modify many other members of the AGC kinase family such as PKCs and SGK. We will continue to utilize a combination of biochemical and genetic approaches to study the regulation and physiological roles of MEKK2, MEKK3, and Sin1-mTOR signaling in immune and cardiovascular system.
- Xing Chang, Fang Liu, Xiaofang Wang, and Su B. MEKK2 and MEKK3 regulate TGF-b-mediated helper T cell differentiation. Immunity. 34: 201-212, 2011.
mTOR Complex 2 Targets Akt for Proteasomal Degradation via Phosphorylation at the Hydrophobic Motif.
You-Tong Wu, Weiming Ouyang, Adam S Lazorchak, Dou Liu, Han-Ming Shen, and Su B. mTOR Complex 2 Targets Akt for Proteasomal Degradation via Phosphorylation at the Hydrophobic Motif. J Biol Chem. 286: 14190-14198, 2011.
- Xiaofang Wang, Fan Zhang, Fanping Chen, Dou Liu, Yi Zheng, Yongliang Zhang, Chen Dong, and Su B. MEKK3 regulates IFNg production in T cells through the Rac1/2 dependent MAPK cascades. J. Immunol. 186: 5791-5800, 2011.
- Adam S Lazorchak, Dou Liu, Valeria Facchinetti, Annarita Di Lorenzo, William C Sessa, David G Schatz & Su B. Sin1 suppresses rag1/2 and il7r gene expression through Akt2 in B cells. Mol. Cell. 39: 433-443, 2010. PMCID2957800
- Xiaofang Wang, Yongliang Zhang, Valeria Facchinetti, Yuan Zhuang, and Su B. MEKK3 Is Essential for Lymphopenia-Induced T cell Proliferation and Survival. J. Immunol. 182(6): 3597-3608, 2009. PMCID2923428
- Valeria Facchinetti, Weiming Ouyang, Hua Wei, Nelyn Soto, Adam Lazorchak, Christine Gould, Carolyn Lowry, Alexandra C. Newton, Yuxin Mao, Robert Q. Miao, William C. Sessa, Jun Qin, Pumin Zhang, Su B, and Estela Jacinto. The mammalian target of rapamycin complex 2 controls folding and stability of Akt and protein kinase C. EMBO J. 27(14):1932-43, 2008.
- Deng Y, Yang J, McCarty M, Su B. MEKK3 is required for endothelium function but is not essential for tumor growth and angiogenesis. Am J Physiol Cell Physiol. 293(4):1404-11, 2007.
- Jacinto E, Facchinetti V, Liu D, Soto N, Wei S, Jung SY, Huang Q, Qin J, Su B. SIN1/MIP1 maintains rictor-mTOR complex integrity and regulates Akt phosphorylation and substrate specificity. Cell. 127(1):125-37. 2006.
- Zhang, D., et al. (2006). Identification of MEKK2/3 serine phosphorylation site targeted by the Toll-like receptor- and stress-pathways. EMBO J. 25:97-107.