Kunxin LuoAssociate Professor of Cell and Developmental Biology**And Staff Scientist, Lawrence Berkeley National Laboratory, Division of Life Sciences E-mail: kluo@berkeley.edu
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Research Interests
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We are interested in the signal transduction pathways downstream of the transforming growth factor β (TGFβ) receptors and the role these pathways play in regulation of mammalian epithelial cell growth, differentiation, apoptosis and carcinogenesis. We wish to understand how TGFβ induces a wide range of biological activities and identify components of the TGFβ receptor signaling pathways.
Current Projects
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The TGFβ family of cytokines plays important roles in tumor suppression, cell differentiation and tissue morphogenesis, and extracellular matrix production. TGFβ exerts its diverse effects through the cell surface types I and II receptors (TβRI and TβRII), which possess serine/threonine kinase activities, and downstream Smad proteins. Loss of functional TGFβ receptors and/or Smad proteins results in abnormal cell overproliferation, and this may contribute to the cause and progression of many types of human cancer including breast cancer, lymphoma, colon cancer and pancreatic cancer. A better understanding of the mechanism of TGFβ receptor signal transduction is therefore a crucial first step towards a better understanding and treatment of human cancer.
Current model of TGFβ signaling: Binding of TGFβ to the cell surface receptors results in activation of receptor kinases, which then phosphorylate and activate downstream Smad2 and Smad3 proteins. Phosphorylated Smad2 and Smad3 then form heteromeric complexes with Smad4 and translocate to the nucleus where they activate transcription of multiple TGFβ response genes.
We are interested in understanding how this relatively simple pathway mediates such a wide variety of TGFβ-induced signals and what role this pathway plays in mammary gland development and breast cancer. Our current research is designed to address the following questions:
How does Smad proteins activate a wide range of TGFβ-induced biological functions and how is this signaling pathway regulated? Our working hypothesis is that the Smad proteins activate multiple TGFβ target genes by interacting with different cellular partners. Our goal is, then, to identify these cellular partners and to investigate the roles these molecules play in regulation of Smad function. Using biochemical approaches, we have identified several molecules interacting with different Smad proteins. Interestingly, two of the molecules we identified, Ski and SnoN, are both oncogene products. These oncoproteins, when overexpressed, can induce transformation of cells. We found that Ski and SnoN can interact with Smad2, Smad3 and Smad4 on a TGFβ responsive element and repress the ability of the Smads to activate TGFβ target genes. Overexpression of Ski or SnoN renders cells resistant to TGFβ-induced growth inhibition. This ability to inactivate the tumor suppressor activity of the Smads may be partially responsible for the transforming activity of Ski and SnoN. Current studies focus on how expression of Ski and SnoN is regulated in normal and cancerous cells, and how interaction of Ski/SnoN with the Smad proteins regulates carcinogenesis and embryonic development. We are also investigating the function of other Smad-interacting proteins we have identified.What is the role of TGFβ signaling pathway in mammary epithelial cell differentiation and breast cancer? In vitro studies using tissue culture cell lines allow us to carry out biochemical studies to understand the function and regulation of individual signaling molecules. Once this goal is achieved, we wish to apply this knowledge to an in vivo system and try to understand the role of the signaling pathway in a complex biological process. For this, we will use mammary epithelial cell differentiation and breast cancer as a model system. By introducing dominant negative and constitutive active mutants of TGFβ signaling molecules, we will attempt to address the importance of TGFβ signaling in different stages of mammary epithelial cell differentiation and how deregulation of TGFβ signaling contributes to breast cancer.
Selected Publications
- The integral inner nuclear membrane protein MAN1 physically interacts with the R-Smad proteins to repress signaling by the transforming growth factor-β superfamily of cytokines. [D. Pan, L.D. Estevez-Salmeron, S.L. Stroschein, X. Zhu, J. He, S. Zhou, and K. Luo (2004) Submitted.]
Ski and SnoN: negative regulators of TGFβ signaling. [K. Luo (2004) Curr. Op. Gen. Dev., 14, 65-70.]
Akt interacts directly with Smad3 to regulate the sensitivity to TGFβ-induced apoptosis. [A. Conery, Y. Cao, E.A. Thompson, C.M. Townsend Jr, T.C. Ko, and K. Luo (2004) Nature Cell Biology, 6, 366-72.]
The transforming activity of Ski is dependent on their ability to interact with the Smad proteins. [J. He, S. Tegen, A. R. Krawitz, S. G. Martin, and K. Luo (2003) J. Biol. Chem. 278, 30540-30547.]
Structural mechanism of Smad4 recognition by the nuclear oncoprotein Ski: Insights on Ski-mediated repression of TGF-β signaling. [J.-W. Wu, A. R. Krawitz, J. Chai, W. Li, F. Zhang, K. Luo and Y. Shi (2002) Cell 110, 357-367.]
Smad3 recruits the anaphase promoting complex for ubiquitination and degradation of SnoN [S. L. Stroschein, S. Bonni, J. L. Wrana and K. Luo (2001) Genes & Development 15, 2822-2836]
TGFβ induces assembly of a Smad2-Smurf2 ubiquitin ligase complex that targets SnoN for degradation. [S. Bonni, H.-R. Wang, C. G. Causing, P. Kavsak, S. L. Stroschein, K. Luo and J. L. Wrana (2001) Nature Cell Biology 3, 587-595]
Ski represses BMP signaling to induce neural cell fate. [W. Wang, F. V. Mariani, R. M. Harland and K. Luo (2000) Proc. Natl. Acad. Sci. 97, 14394-14399]
Negative feedback regulation of TGFβ signaling by the SnoN oncoprotein. [S. L. Stroschein, W. Wang, S. Zhou, Q. Zhou, and K. Luo (1999) Science 286, 771-774]
Last Updated 9/20/2004
