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Avery August
Assistant Professor of Immunology

101 Henning Bldg
814-863-3539
axa45@psu.edu


Education:

Postdoctoral training, Laboratory of Molecular Oncology, The Rockefeller University, New York (with Dr. Hidesaburo Hanafusa)

Ph.D., Immunology, Cornell University (with Dr. Bo Dupont)

B.S., Medical Technology, California State University, Los Angeles


Research:

Regulation of receptor and nonreceptor tyrosine kinases and phosphatases; downstream and developmental targets of tyrosine kinases and phosphatases; regulation of lymphocyte development by tyrosine kinases

We are interested in the role of TKs in cell growth and lymphoid activation, specifically the Src and Tec families of nonreceptor TKs. One approach to studying the roles of these kinases is to specifically activate them on demand at relevant periods. Methods to independently activate these kinases would help in this regard. We are therefore developing strategies to specifically activate individual intracellular TKs with defined signals. These “regulatable” TKs will then be expressed in cells or in animals and turned on at specific periods during cell growth or development to determine their effects on model systems. Specifically, we use Lck as an example of Src family kinases and Itk as an example of the Tec family of kinases, to examine the effect of activating these kinases in cell culture as well as during specific periods during T- and B cell development.

Regulation of downstream signals and development by Src family kinases

Src family kinases are involved in the signaling pathways of a number of receptor systems. Roles in the vertebrate immune and other systems for Src kinases are particularly well described, where lack of individual Src kinases produces defects in particular cell types. For example, mice lacking Lck have poorly developed T-cell compartments. Current models suggest that these kinases represent the first tier of TKs activated by immune receptors. Once activated, these kinases activate a cascade of other TKs, such as members of the Tec (for example, Itk, see below) and Syk family of TKs, leading to specific effects in immune cells. Using methods to specifically activate the Src family kinase Lck, we are examining the effects of activation of Lck in tissue culture and during mouse develop-ment by expressing them using T- or B-cell-specific promoters.

Regulation of downstream signals and development by Itk (Tec family kinases)

Itk is a member of the Tec family of TKs. Mice lacking Itk have T-cell defects, including reduced intracellular calcium increases during T cell activation and defective T H2 development. Understanding the specific downstream activities of these kinases is crucial to understanding how they impact lymphoid activation and development.

We have previously shown that Itk is activated during T-cell receptor (TcR) signaling in T cells, and this activation requires the Src family kinase Lck. We are further examining the mechanism of TcR regulation of Itk activity, whether additional signaling molecules are required, and whether the different TcR-associated chains differ in their ability to activate Itk. We have also shown that the activation of Itk by Lck occurs via the lipid kinase (PI 3-kinase) mediated recruitment of Itk to the cell membrane, where it is then acted upon by Lck. To examine downstream signals that emanate specifically from Itk during T cell activation and its role in T cell develop-ment, we are also developing methods to either activate this kinase independently of either Lck or PI 3-kinase or separate the effects of the two kinases by using specific inhibitors. By activating the kinase in temporally controlled ways, the role of Itk will be elucidated during T cell activation in vitro and in vivo. The results of these experiments should point to novel signaling nodes in the signaling pathways of Tec and Src family kinases, which, by either activating or inhibiting specific downstream signals, will selectively affect specific subsets of processes regulated by Src and Tec family kinases. These in turn may reveal mechanisms to specifically regulate T cell function in diseases where they have a pathological role.


Publications:

T. Ouchi, A. N. A. Monteiro, A. August, S. A. Aaronson, and H. Hanafusa. 1998. BRCA1 regulates p53-dependent gene expression. Proc. Natl. Acad. Sci. 95:2302.

A. August, A. Sadra, B. Dupont, and H. Hanafusa. 1997. Src induced activation of Inducible T cell Kinase (ITK) requires PI3 kinase activity and the Pleckstrin Homology domain of inducible T cell kinase. Proc. Natl. Acad. Sci. 94:11227.

P. D. King, J. M. C. Teng, A. Sadra, X.-R. Liu, A. Han, A. Selvakumar, A. August, and B. Dupont. 1997. Analysis of CD28 cytoplasmic tail residues as regulators and substrates for protein tyrosine kinases, EMT and LCK. J. Immunol. 158:581.

A. N. A. Monteiro,* A. August,* and H. Hanafusa. 1996. A transcriptional activation function for BRCA1 C-terminal region. Proc. Natl. Acad. Sci. 93:13595.

S. Gibson, A. August, Y. Kawakami, T. Kawakami, B. Dupont, and G. B. Mills. 1996. The EMT/ITK tyrosine kinase is activated during T cell receptor signaling: LCK is required for optimal activation of EMT. J. Immunol. 156:2716.

S. Gibson,* A. August,* D. Branch, B. Dupont, and G. B. Mills. 1996. Functional LCK is required for optimal CD28-mediated activation of the TEC family tyrosine kinase EMT/ITK . J. Biol. Chem. 271:7079.

A. August, S. Gibson, Y. Kawakami, T. Kawakami, G. B. Mills, and B. Dupont. 1994. CD28 is associated with and induces immediate tyrosine phosphorylation and activation of Tec family kinase ITK/EMT in human Jurkat leukemic cell line. Proc. Natl. Acad. Sci. USA 91:9347.

*equal contributors

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