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Assistant Professor of Immunology
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
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
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
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.
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.
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.
A. N. A. Monteiro,* A. August,* and H. Hanafusa. 1996. A transcriptional
activation function for BRCA1 C-terminal region. Proc. Natl. Acad. Sci.
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.
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.
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