David Straus, Ph.D.
Associate Professor

Phone: (804) 628-0247
Dept. Fax: (804) 828-9946
e-mail: dbstraus@vcu.edu

Address:
Department of Microbiology & Immunology
Virginia Commonwealth University
P.O. Box 980678
1217 E. Marshall St., 231 Medical Sciences Building
Richmond, VA 23298-0678

Professional Experience

• B.A., 1982, Haverford College
• Ph.D., 1989, University of Wisconsin - Madison
• Postdoctoral Studies: 1989 -1994, University of California - San Francisco

Research Interests

Cell growth, differentiation, and function are dynamic processes, regulated by a large number of external signals.  In most cases the means by which signals specify cell fate and function are unknown.  Understanding how cells recognize and respond to external signals is essential to a basic understanding of biological function, and can provide avenues for the development therapeutic applications.

           T lymphocytes are critical component of the immune system and an excellent model for examining issues in cell signaling.  The development and function of T lymphocytes is tightly controlled by signals conveyed through cell-surface receptors, in particular the antigen receptor.  Although many signaling pathway components have been uncovered, the basic mechanism responsible for initiation of receptor signaling remains unknown.  Additionally, how receptor signals are coupled to intracellular signaling pathways, which specify cell function in response to a variety of signals, is not well understood.  We are using several different approaches in order to address these issues at the molecular, cellular and whole organism level.

In previous work we have carried out biochemical and molecular genetic analyses of antigen receptor signaling.  Our studies established a central role for Src family tyrosine kinases in T lymphocyte signaling using a signaling mutant of the Jurkat T cell line called JCaM1 (1).

 

Left: Three-dimensional structure of c-Src tyrosine kinase. Right: Fluorescence microscopy shows the Src-family kinase, Lck (red) localizing to the interface between T cells and antigen presenting cells.

The JCaM1 cell line is defective in Src kinase activity, which has allowed us to examine the role of these kinases in specific signaling processes using site-specific mutants.  Our work has shown that the Src family kinase Lck regulates the MAP Kinase signaling pathway, and cell fate specification, through the function of one of its protein interaction domains, the SH3 domain (2).

Above: Model of Lck function in T cell antigen receptor (TCR) signaling.

We have expanded these studies to assess the role of this regulatory mechanism in T lymphocyte development and mature T cell function by generating gene targeted mice carrying an Lck SH3 domain mutation (3, 4). 

In addition, we have also investigated the mechanism of receptor signal initiation and found that regulation of Lck kinase activity controls signal strength, but not initiation of receptor signaling (5).  In contrast, preliminary analysis indicates that the amino-terminal domain of Lck is essential for initiation of receptor signaling without altering kinase activity.  In separate studies we have also investigated specificity and redundancy within kinase families by comparing the ability of two closely related Src kinases, Lck and Fyn, to mediate T cell signaling.  We have observed that signaling by each kinase generates unique lymphocyte activation characteristics, suggesting that T lymphocyte immune function may be determined by the specific kinase used to mediate receptor signaling (6).

Selected Publications:

1. Straus D., and Weiss, A.  Genetic evidence for the involvement of the lck tyrosine kinase in signal transduction through the T cell antigen receptor.  Cell, 70:585-593, 1992.

2.  Denny, M., Kaufman, H., Chan, A. C., and Straus, D.  The Lck SH3 domain is required for activation of the MAP kinase pathway, but not the initiation of TCR signaling.  Journal of Biological Chemistry 274: 5146-5152, 1999.

3.  Rudd, M. L., Tua-Smith, A., and Straus, D. B.  Lck SH3 domain function is required for T cell receptor signals regulating thymocyte development. Molecular and Cellular Biology 26:7892-900.  2006.

4. McCoy, M. E., Finkelman, F. D., and Straus, D. B. Th2 immunity and peripheral T cell function is regulated by the p56lck SH3 domain.  Journal of Immunology (Submitted for publication).

5.  Straus, D.B., Rudd, M. L., Tua-Smith, A., Patterson, J.  Z., and Denny, M. F.  Lck activation loop phosphorylation regulates the strength of T-cell antigen receptor signaling, but is not required for initiation.  Journal of Immunology.  (Submitted for publication).

6.  Denny, M. F., Patai, B., and Straus, D. B.  Differential T cell antigen receptor signaling mediated by the Src-family kinases Lck and Fyn.  Molecular and Cellular Biology, 20:1426-1435, 2000.

Virginia Commonwealth University | School of Medicine
Date Last Modified: 09/03/2009
Contact Department Webmaster